Nasal drug products and methods of their use

ABSTRACT

Drug products adapted for nasal delivery, comprising a pre-primed device filled with a pharmaceutical composition comprising an opioid receptor antagonist, are provided. Methods of treating opioid overdose or its symptoms with the inventive drug products are also provided.

This application is a continuation of U.S. application Ser. No.14/942,344, filed Nov. 16, 2015, which is a continuation-in-part of U.S.application Ser. No. 14/659,472, filed Mar. 16, 2015, which claims thebenefit of U.S. Provisional Application No. 61/953,379, filed Mar. 14,2014, the disclosures of which are hereby incorporated by reference asif written herein in their entirety.

Provided are drug products adapted for nasal delivery comprising apre-primed device and a pharmaceutical composition comprising an opioidreceptor antagonist, pharmaceutical compositions comprising an opioidreceptor antagonist, and methods of use thereof.

Opioid receptors are G protein-coupled receptors (GPCRs) that areactivated both by endogenous opioid peptides and by clinically importantalkaloid analgesic drugs such as morphine. There are three principaltypes of opioid receptors: the δ-opioid receptor, the κ-opioid receptor,and the μ-opioid receptor. Opioids depress respiration, which iscontrolled principally through medullary respiratory centers withperipheral input from chemoreceptors and other sources. Opioids produceinhibition at the chemoreceptors via μ-opioid receptors and in themedulla via μ- and δ-opioid receptors. While there are a number ofneurotransmitters mediating the control of respiration, glutamate andγ-aminobutyric acid (GABA) are the major excitatory and inhibitoryneurotransmitters, respectively. This explains the potential forinteraction of opioids with benzodiazepines and alcohol: bothbenzodiazepines and alcohol facilitate the inhibitory effect of GABA atthe GABAA receptor, while alcohol also decreases the excitatory effectof glutamate at NMDA receptors. Oxycodone and other opioid painkillers,as well as heroin and methadone are all implicated in fatal overdose.Heroin has three metabolites with opioid activity. Variation in theformation of these metabolites due to genetic factors and the use ofother drugs could explain differential sensitivity to overdose.Metabolites of methadone contribute little to its action. However,variation in rate of metabolism due to genetic factors and other drugsused can modify methadone concentration and hence overdose risk. Thedegree of tolerance also determines risk. Tolerance to respiratorydepression is less than complete, and may be slower than tolerance toeuphoric and other effects. One consequence of this may be a relativelyhigh risk of overdose among experienced opioid users. While agonistadministration modifies receptor function, changes (usually in theopposite direction) also result from use of antagonists, for example,supersensitivity to opioids following a period of administration ofantagonists such as naltrexone.

In the United States, mortality rates closely correlate with opioidsales. In 2008, approximately 36,450 people died from drug overdoses. Atleast 14,800 of these deaths involved prescription opioid analgesics.Moreover, according to the Substance Abuse and Mental Health ServicesAdministration, the number/rate of Americans 12 years of age and olderwho currently abuse pain relievers has increased by 20 percent between2002 and 2009. In New York City, between 1990 and 2006, the fatalityrate from prescription opioids increased seven-fold, from 0.39 per100,000 persons to 2.7. Drugs classed as prescription opioids in thisstudy include both typical analgesics, such as OxyContin® (oxycodone HClcontrolled-release) and methadone (used in the treatment of dependenceon other opioids such as heroin and also prescribed for pain), but theincrease in the rate of drug overdose over the 16 years of the study wasdriven entirely by overdoses of typical analgesics. Over the same timeperiod, methadone overdoses remained stable, and overdoses from heroindeclined. Whites were more likely than blacks and Latinos to overdose onthese analgesics, and deaths mostly occurred in neighborhoods with lowerrates of poverty, suggesting differential access to doctors who canwrite painkiller prescriptions may be a driving force behind the racialdisparity. (Cerdá et al. “Prescription opioid mortality trends in NewYork City, 1990-2006: Examining the emergence of an epidemic,” Drug andAlcohol Dependence Volume 132, Issues 1-2, 1 Sep. 2013, 53-62.)

Naloxone is an opioid receptor antagonist that is approved for use byinjection for the reversal of opioid overdose and for adjunct use in thetreatment of septic shock. It is currently being used mainly inemergency departments and in ambulances by trained medicalprofessionals. There have been efforts to expand its use by providingthe drug to some patients with take-home opioid prescriptions and thosewho inject illicit drugs, potentially facilitating earlieradministration of the drug. The UN Commission on Narcotics Drugs“encourages all Member States to include effective elements for theprevention and treatment of drug overdose, in particular opioidoverdose, in national drug policies, where appropriate, and to sharebest practices and information on the prevention and treatment of drugoverdose, in particular opioid overdose, including the use of opioidreceptor antagonists such as naloxone.”

U.S. Pat. No. 4,464,378 describes a method for eliciting an analgesic ornarcotic antagonist response in a warm-blooded animal, which comprisesadministering intranasally (IN) to said animal to elicit a narcoticantagonist response, a narcotic antagonist effective amount of naloxone.WO 82/03768 discloses a composition that contains 1 mg of naloxonehydrochloride per 0.1 ml of solution adapted for nasal administrationused in the treatment of narcotic induced respiratory depression(overdose) at a dosage approximately the same as that employed forintravenous (IV), intramuscular (IM) or subcutaneous (SQ)administration. WO 00/62757 teaches pharmaceutical compositions for INor oral (PO) administration which comprise an opioid antagonist, such asnaloxone for application by spray in the reversal of opioid depressionfor treatment of patients suffering from opioid over-dosage, wherein thespray applicator is capable of delivering single or multiple doses andsuitable dosage units are in the range of 0.2 to 5 mg.

The use of nasal naloxone is not without controversy. For instance,Loimer et al. (International Journal of Addictions, 29(6), 819-827,1994) reported that the nasal administration of naloxone is as effectiveas the intravenous route in opiate addicts, however, Dowling et al.(Ther Drug Monit, Vol 30, No 4, August 2008) reported that naloxoneadministered intranasally displays a relative bioavailability of 4% onlyand concluded that the IN absorption is rapid but does not maintainmeasurable concentrations for more than an hour.

One early study of 196 consecutive patients with suspected opioidoverdose conducted in an urban out-of-hospital setting, had shown themean interval from emergency medical services (EMS) arrival to arespiratory rate of ≧10 breaths/min was 9.3±4.2 min with administrationof naloxone 0.4 mg IV, versus 9.6±4.58 min with administration ofnaloxone 0.8 mg SQ. The authors concluded that the slower rate ofabsorption via the SQ route was offset by the delay in establishing anIV line. (Wanger et al., Intravenous vs subcutaneous naloxone forout-of-hospital management ofpresumed opioid overdose. Acad Emerg Med.1998 April; 5(4):293-9).

The Denver Health Paramedic system subsequently investigated theefficacy and safety of atomized intranasal naloxone for the treatment ofsuspected opiate overdose (Barton, et al., Efficacy of intranasalnaloxone as a needleless alternative for treatment of opioid overdose inthe prehospital setting. J Emerg Med, 2005. 29(3): p. 265-71). All adultpatients encountered in the prehospital setting as suspected opiateoverdose, found down, or with altered mental status who met the criteriafor naloxone administration were included in the study. IN naloxone (2mg) was administered immediately upon patient contact and before IVinsertion and administration of IV naloxone (2 mg). Patients were thentreated by EMS protocol. The main outcome measures were: time of INnaloxone administration, time of IV naloxone administration, time ofappropriate patient response as reported by paramedics. Ninety-fivepatients received IN naloxone and were included in the study. A total of52 patients responded to naloxone by either IN or IV, with 43 (83%)responding to IN naloxone alone. Seven patients (16%) in this grouprequired further doses of IV naloxone. The median times from arrival atpatient side to awakening and from administration of the IN naloxone topatient awakening were 8.0 minutes and 3.0 minutes respectively.

The Drug Overdose Prevention and Education (DOPE) Project was the firstnaloxone prescription program (NPP) established in partnership with acounty health department (San Francisco Department of Public Health),and is one of the longest running NPPs in the USA. From September 2003to December 2009, 1,942 individuals were trained and prescribed naloxonethrough the DOPE Project, of whom 24% returned to receive a naloxonerefill, and 11% reported using naloxone during an overdose event. Of 399overdose events where naloxone was used, participants reported that 89%were reversed. In addition, 83% of participants who reported overdosereversal attributed the reversal to their administration of naloxone,and fewer than 1% reported serious adverse effects. Findings from theDOPE Project add to a growing body of research that suggests thatintravenous drug users (IDUs) at high risk of witnessing overdose eventsare willing to be trained on overdose response strategies and usetake-home naloxone during overdose events to prevent deaths (Enteen, etal., Overdose prevention and naloxone prescription for opioid users inSan Francisco. J Urban Health. 2010 December; 87(6):931-41).

Another reported study reviewed EMS and hospital records before andafter implementation of a protocol for administration of intranasalnaloxone by the Central California EMS Agency in order to compare theprehospital time intervals from patient contact and medicationadministration to clinical response for IN versus intravenous IVnaloxone in patients with suspected narcotic overdose. The protocol forthe treatment of opioid overdose with intranasal naloxone was asfollows: “Intranasal (IN)—Administer 2 mg intranasally (1 mg pernostril) using mucosal atomizer device (MAD™) if suspected narcoticintoxication and respiratory depression (rate 8 or less). This dose maybe repeated in 5 minutes if respiratory depression persists.Respirations should be supported with a bag valve mask until respiratoryrate is greater than 8. Intramuscular (IM)—Administer 1 mg if unable toadminister intranasally (see special considerations). May repeat once in5 minutes. Intravenous (IV)—Administer 1 mg slow IV push if no responseto intranasal or IM administration after 10 minutes. Pediatric dose—0.1mg/kg intranasally, if less than 10 kg and less than 1 year old”.Patients with suspected narcotic overdose treated in the prehospitalsetting over 17 months, between March 2003 and July 2004 were included.Paramedics documented dose, route of administration, and positiveresponse times using an electronic record. Clinical response was definedas an increase in respiratory rate (breaths/min) or Glasgow Coma Scalescore of at least 6. Main outcome variables included time frommedication to clinical response and time from patient contact toclinical response. Secondary variables included numbers of dosesadministered and rescue doses given by an alternate route. Between-groupcomparisons were accomplished using t-tests and chi-square tests asappropriate. One hundred fifty-four patients met the inclusion criteria,including 104 treated with IV and 50 treated with IN naloxone. Clinicalresponse was noted in 33 (66%) and 58 (56%) of the IN and IV groups,respectively (p=0.3). The mean time between naloxone administration andclinical response was longer for the IN group (12.9 vs. 8.1 min,p=0.02). However, the mean times from patient contact to clinicalresponse were not significantly different between the IN and IV groups(20.3 vs. 20.7 min, p=0.9). More patients in the IN group received twodoses of naloxone (34% vs. 18%, p=0.05), and three patients in the INgroup received a subsequent dose of IV or IM naloxone. (Robertson etal., Intranasal naloxone is a viable alternative to intravenous naloxonefor prehospital narcotic overdose. Prehosp Emerg Care. 2009October-December; 13(4):512-5).

In August 2006, the Boston Public Health Commission passed a publichealth regulation that authorized an opioid overdose prevention programthat included intranasal naloxone education and distribution of thespray to potential bystanders. Participants were instructed by trainedstaff to deliver 1 mL (1 mg) to each nostril of the overdose victim.After 15 months, the program had provided training and intranasalnaloxone to 385 participants who reported 74 successful overdosereversals (Doe-Simkins et al. Overdose prevention education withdistribution of intranasal naloxone is a feasible public healthintervention to address opioid overdose. Am J Public Health. 2009;99:788-791).

Overdose education and nasal naloxone distribution (OEND) programs arecommunity-based interventions that educate people at risk for overdoseand potential bystanders on how to prevent, recognize and respond to anoverdose. They also equip these individuals with a naloxone rescue kit.To evaluate the impact of OEND programs on rates of opioid related deathfrom overdose and acute care utilization in Massachusetts, aninterrupted time series analysis of opioid related overdose death andacute care utilization rates from 2002 to 2009 was performed comparingcommunity-year strata with high and low rates of OEND implementation tothose with no implementation. The setting was nineteen Massachusettscommunities (geographically distinct cities and towns) with at leastfive fatal opioid overdoses in each of the years 2004 to 2006. OEND wasimplemented among opioid users at risk for overdose, social serviceagency staff, family, and friends of opioid users. OEND programsequipped people at risk for overdose and bystanders with nasal naloxonerescue kits and trained them how to prevent, recognize, and respond toan overdose by engaging emergency medical services, providing rescuebreathing, and delivering naloxone. Among these communities, OENDprograms trained 2,912 potential bystanders who reported 327 rescues.Both community-year strata with 1-100 enrollments per 100,000 population(adjusted rate ratio 0.73, 95% confidence interval 0.57 to 0.91) andcommunity-year strata with greater than 100 enrollments per 100,000population (0.54, 0.39 to 0.76) had significantly reduced adjusted rateratios compared with communities with no implementation. Differences inrates of acute care hospital utilization were not significant. Opioidoverdose death rates were reduced in communities where OEND wasimplemented. This study provides observational evidence that by trainingpotential bystanders to prevent, recognize, and respond to opioidoverdoses, OEND is an effective intervention (Walley et al., Opioidoverdose rates and implementation of overdose education and nasalnaloxone distribution in Massachusetts: interrupted time seriesanalysis. BMJ 2013; 346:f174).

Naloxone prescription programs are also offered by community-basedorganizations in Los Angeles and Philadelphia. Programs in both citiestarget IDUs. Studies which recruited 150 IDUs across both sites forin-depth qualitative interviews compared two groups of IDUs, those whohad received naloxone prescriptions and those who had never receivednaloxone prescriptions. In both L.A. and Philadelphia, IDUs reportedsuccessfully administering naloxone to reverse recently witnessedoverdoses. Reversals often occurred in public places by both housed andhomeless IDUs. Despite these successes, IDUs frequently did not havenaloxone with them when they witnessed an overdose. Two typical reasonsreported were naloxone was confiscated by police, and IDUs did not feelcomfortable carrying naloxone in the event of being stopped by police.Similarly, some untrained IDUs reported discomfort with the idea ofcarrying naloxone on them as their reason for not gaining aprescription.

A randomized trial comparing 2 mg naloxone delivered intranasally with amucosal atomizer to 2 mg intramuscular naloxone was reported by Kelly etal., in 2005 (Med J Aust. 2005 Jan. 3; 182(1):24-7). The study involved155 patients (71 IM and 84 IN) requiring treatment for suspected opiateoverdose and attended by paramedics of the Metropolitan AmbulanceService (MAS) and Rural Ambulance Victoria in Victoria, Australia. TheIM group had more rapid response than the IN group, and were more likelyto have more than 10 spontaneous respirations per minute within 8minutes (82% v. 63%; P=0.0173). There was no statistically significantdifference between the IM and IN groups for needing rescue naloxone (13%[IM group] v. 26% [IN group]; P=0.0558). The authors concluded that INnaloxone is effective in treating opiate-induced respiratory depression,but is not as effective as IM naloxone.

Kerr et al. (Addiction. 2009 December; 104(12):2067-74) disclosedtreatment of heroin overdose by intranasal administration of naloxoneconstituted in a vial as a preparation of 2 mg in 1 mL. Participantsreceived 1 mg (0.5 ml) in each nostril. The rate of response within 10minutes was 60/83 (72.3%) for 2 mg IN naloxone versus 69/89 (77.5%) for2 mg IM naloxone. The mean response times were 8.0 minutes and 7.9minutes for IN and IV naloxone respectively. Supplementary naloxone wasadministered to fewer patients who received IM naloxone (4.5%) than IN(18.1%).

WO2012156317 describes a study in which naloxone, 8 mg and 16 mg, wasadministered as 400 μL IN (200 μL per nostril). The administration wasperformed as follows: The pump of the nasal spray was primed by removingthe cap and pressing downward. This is repeated at least 6 times oruntil a fine spray appears; priming is done just prior to dosing. Thesubject is in a standing or upright position and should gently blow thenose to clear the nostrils. The subject should tilt the head forwardslightly and gently close one nostril by pressing the outside of thenose with a finger on the nostril to be closed. The device is insertedinto the open nostril and it is sprayed 2 times into the nostril. Thesubject should gently breath inward through the nostril, the device isremoved, and the steps are repeated for the other nostril. The meanT_(max) values were reported to be 0.34 h (20.4 min) and 0.39 h (23.4min) for the 8 and 16 mg doses respectively.

Wermeling (Drug Deliv Transl Res. 2013 Feb. 1; 3(1): 63-74) teaches thatthe initial adult dose of naloxone in known or suspected narcoticoverdose is 0.4 to 2 mg, which may be repeated to a total dose of 10 mgand that the current formulations of naloxone are approved forintravenous (IV), intramuscular (IM) and subcutaneous (SC)administration, with IV being the recommended route. Wermeling alsopredicts that a 2 mg nasal solution dose of naloxone will likely have aC_(max) of 3-5 ng/mL and a t_(max) of approximately 20 minutes.

Since the onset of action of naloxone used in opioid overdose casesshould be as fast as possible, naloxone is thus far mainly administeredintravenously or intramuscularly by emergency health care personnel. Dueto a high first pass metabolism, oral dosage forms comprising naloxonedisplay a low bioavailability and thus seem to be not suitable for suchpurposes. The administration of naloxone via injection into the bloodstream or into the muscle requires first of all trained medicalpersonnel (for intravenous injection) or a trained carer (forintramuscular injection). Secondly, depending on the constitution of theaddict and the period of intravenous drug abuse, it can be particularlydifficult to find access into a vein of the addict's body foradministering naloxone intravenously. Clearly, there is a risk ofexposure to blood borne pathogens for the medical personnel or thetrained carer since a large population of drug addicts suffers fromblood borne pathogen induced diseases such as HIV, hepatitis B and C,and the like since accidental needlestick is a serious safety concern.385,000 needle-stick injuries have been estimated to have occurred inthe year 2000 in the US alone (Wilburn, Needlestick and sharps injuryprevention, Online J Issues Nurs 2004, Sep. 30; 9(3):5).

Naloxone has a relatively short half-life of compared to somelonger-acting opioid formulations and so after a typical therapeuticdose of naloxone is administered to an opioid overdose patient there isoften the need to re-administer naloxone, in some cases even severaltimes, and it is important to seek immediate medical attention.

Furthermore, it has been suggested that in view of the growing opioidoverdose crisis in the US, naloxone should be made availableover-the-counter (OTC), which would require a device, such as a nasalspray device, that untrained consumers are able to use safely. A nasalspray device that was pre-filled with a naloxone formulation would alsobe less likely to be confiscated by police than the system developed bysome EMS programs that combines an FDA-approved naloxone injectionproduct with a marketed, medical device called the Mucosal AtomizationDevice.

Thus, there remains a need for durable, easy-to-use, needleless deviceswith storage-stable formulations, that can enable untrained individualsto quickly deliver a therapeutically effective dose of a rapid-actingopioid antagonist to an opioid overdose patient. The therapeuticallyeffective dose should be sufficient to obviate the need for theuntrained individual to administer either a second dose of opioidantagonist or an alternative medical intervention to the patient, and tostabilize the patient until professional medical care becomes available.The devices described herein meet this and other needs.

Provided are devices adapted for nasal delivery of a pharmaceuticalcomposition to a patient, comprising a therapeutically effective amountof an opioid antagonist selected from naloxone and pharmaceuticallyacceptable salts thereof, wherein the device is pre-primed, and whereinthe therapeutically effective amount, is equivalent to about 2 mg toabout 12 mg of naloxone hydrochloride.

Also provided are methods of treating opioid overdose or a symptomthereof, comprising nasally administering to a patient in need thereof atherapeutically effective amount of an opioid antagonist selected fromnaloxone and pharmaceutically acceptable salts thereof, wherein thetherapeutically effective amount is equivalent to about 2 mg to about 12mg of naloxone hydrochloride.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the mean (±SD) naloxone plasma concentration followingadministration of 0.4 mg intramuscular (IM), 2 mg intranasal (IN), and 4mg IN in 14 human subjects.

FIG. 2 shows the mean (±SD) naloxone plasma concentration withlogarithmic transformation following administration of 0.4 mgintramuscular (IM), 2 mg intranasal (IN), and 4 mg IN in 14 humansubjects.

FIG. 3 shows the mean naloxone plasma concentration following singleintranasal administrations (FIG. 3A) and intramuscular injections (FIG.3B) of naloxone to healthy subjects (N=28) over a twelve-hour period.

FIG. 4 shows the mean naloxone plasma concentration following singleintranasal administrations (FIG. 4A) and intramuscular injections (FIG.4B) of naloxone to healthy subjects (N=28) over a four-hour period.

FIG. 5 shows the mean naloxone plasma concentration followingintramuscular injection of 0.4 mg naloxone (FIG. 5A, top) and one sprayof 20 mg/mL naloxone (FIG. 5B, bottom) to healthy male (N=16) and female(N=12) subjects over a twelve-hour period.

FIG. 6 shows the mean naloxone plasma concentration following two spraysof 20 mg/mL (FIG. 6A, top) and one spray of 40 mg/mL (FIG. 6B, bottom)to healthy male (N=16) and female (N=12) subjects over a twelve-hourperiod.

FIG. 7 shows the mean naloxone plasma concentration following two spraysof 40 mg/mL to healthy male (N=16) and female (N=12) subjects over atwelve-hour period.

DETAILED DESCRIPTION OF THE INVENTION

For clarity and consistency, the following definitions will be usedthroughout this patent document.

The term “active ingredient” or “pharmaceutically active compound” isdefined in the context of a “pharmaceutical composition” and is intendedto mean a component of a pharmaceutical composition that provides theprimary pharmacological effect, as opposed to an “inactive ingredient”which would generally be recognized as providing no pharmaceuticalbenefit.

The term “actuation,” as used herein, refers to operation of the devicesuch that the pharmaceutical composition is delivered therefrom.

The term “agonist,” as used herein, refers to as used herein refers to amoiety that interacts with and activates a receptor, and therebyinitiates a physiological or pharmacological response characteristic ofthat receptor. The term “antagonist,” as used herein, refers to a moietythat competitively binds to a receptor at the same site as an agonist(for example, the endogenous ligand), but which does not activate theintracellular response initiated by the active form of the receptor andcan thereby inhibit the intracellular responses by an agonist or partialagonist. An antagonist does not diminish the baseline intracellularresponse in the absence of an agonist or partial agonist. The term“inverse agonist” refers to a moiety that binds to the endogenous formof the receptor or to the constitutively activated form of the receptorand which inhibits the baseline intracellular response initiated by theactive form of the receptor below the normal base level of activitywhich is observed in the absence of an agonist or partial agonist.

The term “antimicrobial preservative,” as used herein, refers to apharmaceutically acceptable excipient with antimicrobial propertieswhich is added to a pharmaceutical composition to maintainmicrobiological stability.

The term “AUC,” as used herein, refers to the area under the drug plasmaconcentration-time curve. The term “AUC_(0-t),” as used herein, refersto the area under the drug plasma concentration-time curve from t=0 tothe last measurable concentration. The term “AUC_(0-∞),” as used herein,refers to the area under the drug plasma concentration-time curveextrapolated to ∞. The term “AUC_(0-t/D),” as used herein, refers to theAUC_(0-t) normalized to 0.4 mg IM naloxone. The term “AUC_(0-∞/D),” asused herein, refers to the AUC_(0-∞) normalized to 0.4 mg IM naloxone

The term “bioavailability (F),” as used herein, refers to the fractionof a dose of drug that is absorbed from its site of administration andreaches, in an unchanged form, the systemic circulation. The term“absolute bioavailability” is used when the fraction of absorbed drug isrelated to its IV bioavailability. It may be calculated using thefollowing formula:

$F = {\frac{{AUC}_{extravascular}}{{AUC}_{intravenous}} \times \frac{{Dose}_{intravenous}}{{Dose}_{extravascular}}}$

The term relative bioavailability (F_(rel)) is used to compare twodifferent extravascular routes of drug administration and it may becalculated using the following formula:

$F_{rel} = {\frac{{AUC}_{{extravascular}\mspace{11mu} 1}}{{AUC}_{{extravascular}\mspace{11mu} 2}} \times \frac{{Dose}_{{extravascular}\mspace{11mu} 2}}{{Dose}_{{extravascular}\mspace{11mu} 1}}}$

The term “clearance (CL),” as used herein, refers to the rate at which adrug is eliminated divided by its plasma concentration, giving a volumeof plasma from which drug is completely removed per unit of time. CL isequal to the elimination rate constant (λ) multiplied by the volume ofdistribution (V_(d)), wherein “V_(d)” is the fluid volume that would berequired to contain the amount of drug present in the body at the sameconcentration as in the plasma. The term “apparent clearance (CL/F),” asused herein, refers to clearance that does not take into account thebioavailability of the drug. It is the ratio of the dose over the AUC.

The term “C_(max),” as used herein, refers to the maximum observedplasma concentration. The term “C_(max/D),” as used herein, refers toC_(max) normalized to 0.4 mg IM naloxone.

The term “coefficient of variation (CV),” as used herein, refers to theratio of the sample standard deviation to the sample mean. It is oftenexpressed as a percentage.

The term “confidence interval,” as used herein, refers to a range ofvalues which will include the true average value of a parameter aspecified percentage of the time.

The term “device,” as used herein, refers to an apparatus capable ofdelivering a drug to patient in need thereof.

The term “delivery time,” as used herein, refers to the amount of timethat elapses between a determination made by a healthcare professional,or an untrained individual that an individual is in need of nasaldelivery of an opioid antagonist and completion of the delivery.

The term “elimination rate constant (λ),” as used herein, refers to thefractional rate of drug removal from the body. This rate is constant infirst-order kinetics and is independent of drug concentration in thebody. λ is the slope of the plasma concentration-time line (on alogarithmic y scale). The term “λ_(z),” as used herein, refers to theterminal phase elimination rate constant, wherein the “terminal phase”of the drug plasma concentration-time curve is a straight line whenplotted on a semilogarithmic graph. The terminal phase is often calledthe “elimination phase” because the primary mechanism for decreasingdrug concentration during the terminal phase is drug elimination fromthe body. The distinguishing characteristic of the terminal eliminationphase is that the relative proportion of drug in the plasma andperipheral volumes of distribution remains constant. During this“terminal phase” drug returns from the rapid and slow distributionvolumes to the plasma, and is permanently removed from the plasma bymetabolism or renal excretion.

The term “equivalent,” as used herein refers to a weight of an opioidantagonist selected from naloxone and pharmaceutically acceptable saltsthereof that is equimolar to a specified weight of naloxonehydrochloride. For example, 8 mg of anhydrous naloxone hydrochloride(molecular weight, 363.84) is equivalent to about 7.2 mg of naloxonefreebase (molecular weight, 327.37), and to about 8.8 mg of naloxonehydrochloride dihydrate (molecular weight 399.87).

The term “filled,” as used herein, refers to an association between adevice and a pharmaceutical composition, for example, when apharmaceutical composition described herein comprising a therapeuticallyeffective amount of an opioid antagonist is present within a reservoirthat forms a part of a device described herein.

The term “hydrate,” as used herein, refers to an opioid antagonistdescribed herein or a salt thereof that further includes astoichiometric or non-stoichiometric amount of water bound bynon-covalent intermolecular forces.

The term “in need of treatment” and the term “in need thereof” whenreferring to treatment are used interchangeably and refer to a judgmentmade by a caregiver (e.g. physician, nurse, nurse practitioner, that apatient will benefit from treatment.

As used herein, two embodiments are “mutually exclusive” when one isdefined to be something which is different than the other. For example,an embodiment wherein the amount of naloxone hydrochloride is specifiedto be 4 mg is mutually exclusive with an embodiment wherein the amountof naloxone hydrochloride is specified to be 2 mg. However, anembodiment wherein the amount of naloxone hydrochloride is specified tobe 4 mg is not mutually exclusive with an embodiment in which less thanabout 10% of said pharmaceutical composition leaves the nasal cavity viadrainage into the nasopharynx or externally.

The term “naloxone,” as used herein, refers to a compound of thefollowing structure:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof. TheCAS registry number for naloxone is 465-65-6. Other names for naloxoneinclude: 17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one;(−)-17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one;4,5a-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one; and(−)-12-allyl-7,7a,8,9-tetrahydro-3,7a-dihydroxy-4aH-8,9c-iminoethanophenanthro[4,5-bcd]furan-5(6H)-one.Naloxone hydrochloride may be anhydrous (CAS Reg. No. 357-08-4) and alsoforms a dihydrate (CAS No. 51481-60-8). It has been sold under variousbrand names including Narcan®, Nalone®, Nalossone®, Naloxona®,Naloxonum®, Narcanti®, and Narcon®.

The term “naltrexone,” as used herein, refers to a compound of thefollowing structure:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof. TheCAS registry number for naltrexone is 16590-41-3. Other names fornaltrexone include:17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one;(5α)-17-(cyclopropylmethyl)-3,14-dihydroxy-4,5-epoxymorphinan-6-one; and(1S,5R,13R,17S)-4-(cyclopropylmethyl)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.01,13.05,17.07,18]octadeca-7(18),8,10-trien-14-one.Naltrexone hydrochloride (CAS Reg. No. 16676-29-2) has been marketedunder the trade names Antaxone®, Depade®, Nalorex®, Revia®, Trexan®,Vivitrex®, and Vivitrol®.

The term “methylnaltrexone,” as used herein, refers to apharmaceutically acceptable salt comprising the cation(5a)-17-(cyclopropylmethyl)-3,14-dihydroxy-17-methyl-4,5-epoxymorphinanium-17-ium-6-onea compound of the following structure:

wherein X⁻ is a pharmaceutically acceptable anion. Methylnaltrexonebromide (CAS Reg. No. 75232-52-7) has been marketed under the trade nameRelistor®.

The term “nalmefene,” as used herein, refers to17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol, acompound of the following structure:

Nalmefene hydrochloride (CAS Reg. No. 58895-64-0) has been marketedunder the trade names Nalmetrene®, Cervene®, Revex®, Arthrene®, andIncystene®.

The term “nostril,” as used herein, is synonymous with “naris.”

The term “opioid antagonist” includes, in addition to naloxone andpharmaceutically acceptable salts thereof: naltrexone, methylnaltrexone,and nalmefene, and pharmaceutically acceptable salts thereof. In someembodiments, the opioid antagonist is naloxone hydrochloride. In someembodiments, the opioid antagonist is naloxone hydrochloride dihydrate.In some embodiments, the opioid antagonist is naltrexone hydrochloride.In some embodiments, the opioid antagonist is methylnaltrexone bromide.In some embodiments, the opioid antagonist is nalmefene hydrochloride.In some embodiments, the nasally administering is accomplished using adevice described herein.

The term “opioid overdose,” as used herein, refers to an acute medicalcondition induced by excessive use of one or more opioids. Symptoms ofopioid overdose include including respiratory depression (includingpostoperative opioid respiratory depression, acute lung injury, andaspiration pneumonia), central nervous system depression (which mayinclude sedation, altered level consciousness, miotic (constricted)pupils), and cardiovascular depression (which may include hypoxemia andhypotension). Visible signs of opioid overdose or suspected opioidoverdose include: unresponsiveness and/or loss of consciousness (won'trespond to stimuli such as shouting, shaking, or rubbing knuckles onsternum); slow, erratic, or stopped breathing; slow, erratic, or stoppedpulse; deep snoring or choking/gurgling sounds; blue or purplefingernails or lips; pale and/or clammy face; slack or limp muscle tone;contracted pupils; and vomiting. Because opioid overdose may bedifficult to diagnose and/or quantify, particularly by a lay person, asused herein, treatment of opioid overdose is meant to include treatmentof suspected opioid overdose in opioid-intoxicated patients. Opioidsthat may induce overdose include, codeine, morphine, methadone,fentanyl, oxycodone HCl, hydrocodone bitartrate, hydromorphone,oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol,tapentadol, and certain narcotic-antagonist analgesics, such as,nalbuphine, pentazocine and butorphanol. In some embodiments, the opioidagonist is in a tamper-proof formulation. In some embodiments, theopioid agonist is in a tamper-resistant formulation. In someembodiments, the opioid agonist is selected from Acurox® OxycodoneDETERx®, Egalet hydrocodone, Egalet morphine, Egalet oxycodone, Exalgo®,Opana®, and Remoxy®.

The term “patient,” as used herein, refers to any subject (preferablyhuman) afflicted with a condition likely to benefit from a treatmentwith a therapeutically effective amount of an opioid antagonist.

The terms “permeation enhancer” and “penetration enhancer,” as disclosedherein, are intended to be equivalent, both referring to an agent whichaids in absorption of a compound, such as through the nasal mucosa.

The term “pharmaceutical composition,” as used herein, refers to acomposition comprising at least one active ingredient; including but notlimited to, salts, solvates and hydrates of the opioid antagonistsdescribed herein, whereby the composition is amenable to use for aspecified, efficacious outcome in a mammal (for example, withoutlimitation, a human).

The term “pre-primed,” as used herein, refers to a device, such as anasal spray which is capable of delivering a pharmaceutical compositionto a patient in need thereof with the first actuation of the spray pump,i.e., without the need to prime the pump prior to dosing, such as byactuating the pump one or more times until a spray appears.

The term “prone,” as used herein, refers to a patient who is lying facedown.

The term “receptor binding or occupancy” refers to a characterization ofthe kinetics between a radioactive drug and receptors or other bindingsites throughout the body, and characterization of the radioactive drugbinding affinity to these receptors.

The term “recovery position,” as used herein, means a position of thehuman body in which a patient lies on his/her side, with a leg or kneeout in front (e.g., to prevent rolling onto his/her stomach) and atleast one hand supporting the head (e.g., to elevate the face tofacilitate breathing and prevent inhalation of vomit).

The term “solvate,” as used herein, refers to an opioid antagonistdescribed herein or a salt, thereof, that further includes astoichiometric or non-stoichiometric amount of a solvent bound bynon-covalent intermolecular forces. Preferred solvents are volatile,non-toxic, and/or acceptable for administration to humans in traceamounts.

The term “sterile filling,” as used herein, refers methods ofmanufacturing the devices and pharmaceutical compositions describedherein, such that the use of preservatives is not required. Sterile drugproducts may be produced using aseptic processing or terminalsterilization. Terminal sterilization usually involves filling andsealing product containers under high-quality environmental conditions.In an aseptic process, the drug product, container, and closure arefirst subjected to sterilization methods separately, as appropriate, andthen brought together.

The term “storage-stable,” as used herein, refers to a pharmaceuticalcomposition in which at least about 95% to 99.5% of the activeingredient remains in an undegraded state after storage of thepharmaceutical composition at specified temperature and humidity for aspecified time, for example, for 12 months at 25° C. and 60% relativehumidity.

The term “supine,” as used herein, refers to a patient who is lying faceup.

The term “t_(1/2)” or “half-life,” as used herein, refers to the amountof time required for half of a drug to be eliminated from the body orthe time required for a drug concentration to decline by half.

The term “tonicity agent,” as used herein, refers to a compound whichmodifies the osmolality of a formulation, for example, to render itisotonic. Tonicity agents include, dextrose, lactose, sodium chloride,calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol,trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycineand the like.

The term “tomography,” as used herein, refers to a process of imaging bysections. The images may be looked at individually, as a series oftwo-dimensional slices or together, as a computer-generatedthree-dimensional representation.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent of a pharmaceutical composition that it compatible with theother ingredients of the formulation and not overly deleterious to therecipient thereof.

The term “substantially free of antimicrobial preservatives” isunderstood by one of ordinary skill in the art to described apharmaceutical composition that may comprise less than 1% w/wantimicrobial preservatives.

The term “therapeutically effective amount,” as used herein, refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, or individual thatis being sought by a researcher, healthcare provider or individual.

The term “T_(max),” as used herein, refers to the time fromadministration of the pharmaceutical compositions described herein tomaximum drug plasma concentration.

The term “untrained individual” refers to an individual administering topatient an opioid antagonist using a device described herein, whereinthe individual is not a healthcare professional and has received notraining in the use of the device, such as through an overdose educationand nasal naloxone distribution (OEND) program.

Opioid Antagonists

Provided are drug products adapted for nasal delivery of an opioidreceptor antagonist. Opioid receptor antagonists are a well recognizedclass of chemical agents. They have been described in detail in thescientific and patent literature. Pure opioid antagonists, such asnaloxone, are agents which specifically reverse the effects of opioidagonists but have no opioid agonist activity.

Naloxone is commercially available as a hydrochloride salt. Naloxonehydrochloride (17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-onehydrochloride), a narcotic antagonist, is a synthetic congener ofoxymorphone. In structure it differs from oxymorphone in that the methylgroup on the nitrogen atom is replaced by an allyl group. Naloxonehydrochloride is an essentially pure narcotic antagonist, i.e., it doesnot possess the “agonistic” or morphine-like properties characteristicof other narcotic antagonists; naloxone does not produce respiratorydepression, psychotomimetic effects or pupillary constriction. In theabsence of narcotics or agonistic effects of other narcotic antagonistsit exhibits essentially no pharmacologic activity. Naloxone has not beenshown to produce tolerance or to cause physical or psychologicaldependence. In the presence of physical dependence on narcotics naloxonewill produce withdrawal symptoms.

While the mechanism of action of naloxone is not fully understood, thepreponderance of evidence suggests that naloxone antagonizes the opioideffects by competing for the same receptor sites. When naloxonehydrochloride is administered intravenously the onset of action isgenerally apparent within two minutes; the onset of action is onlyslightly less rapid when it is administered subcutaneously orintramuscularly. The duration of action is dependent upon the dose androute of administration of naloxone hydrochloride. Intramuscularadministration produces a more prolonged effect than intravenousadministration. The requirement for repeat doses of naloxone, however,will also be dependent upon the amount, type and route of administrationof the narcotic being antagonized. Following parenteral administrationnaloxone hydrochloride is rapidly distributed in the body. It ismetabolized in the liver, primarily by glucuronide conjugation, andexcreted in urine. In one study the serum half-life in adults rangedfrom 30 to 81 minutes (mean 64±12 minutes). In a neonatal study the meanplasma half-life was observed to be 3.1±0.5 hours.

Provided are devices adapted for nasal delivery of a pharmaceuticalcomposition to a patient, comprising a therapeutically effective amountof an opioid antagonist selected from naloxone and pharmaceuticallyacceptable salts thereof, wherein the device is pre-primed, and whereinthe therapeutically effective amount, is equivalent to about 2 mg toabout 12 mg of naloxone hydrochloride. Also provided are devices adaptedfor nasal delivery of a pharmaceutical composition to a patient,comprising a therapeutically effective amount of an opioid antagonistselected from naloxone and pharmaceutically acceptable salts thereof,wherein the device is pre-primed, and wherein the therapeuticallyeffective amount, is equivalent to about 2 mg to about 12 mg of naloxonehydrochloride. In some embodiments, the therapeutically effective amountis equivalent to about 2 mg to about 24 mg of naloxone hydrochloride. Insome embodiments, the therapeutically effective amount is equivalent toabout 2 mg to about 12 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about3 mg to about 18 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 4 mg to about 10mg of naloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 5 mg to about 11 mg of naloxonehydrochloride. In some embodiments, the therapeutically effective amountis equivalent to about 6 mg to about 10 mg of naloxone hydrochloride. Insome embodiments, the therapeutically effective amount is equivalent toabout 4 mg to about 8 mg of naloxone hydrochloride. In some embodiments,the therapeutically effective amount is equivalent to about 7 mg toabout 9 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 3.4 mg ofnaloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 4 mg of naloxone hydrochloride.In some embodiments, the therapeutically effective amount is equivalentto about 5 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 6 mg of naloxonehydrochloride. In some embodiments, the therapeutically effective amountis equivalent to about 7 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about8 mg of naloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 9 mg of naloxone hydrochloride.In some embodiments, the therapeutically effective amount is equivalentto about 10 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 11 mg ofnaloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 12 mg of naloxone hydrochloride.In some embodiments, the opioid antagonist is the only pharmaceuticallyactive compound in pharmaceutical composition. In some embodiments, theopioid antagonist is naloxone hydrochloride. In some embodiments, theopioid antagonist is anhydrous naloxone hydrochloride. In someembodiments, the opioid antagonist is naloxone hydrochloride dihydrate.

While many of the embodiments of the pharmaceutical compositionsdescribed herein will be described and exemplified with naloxone, otheropioid antagonists can be adapted for nasal delivery based on theteachings of the specification. In fact, it should be readily apparentto one of ordinary skill in the art from the teachings herein that thedevices and pharmaceutical compositions described herein may be suitablefor other opioid antagonists. The opioid receptor antagonists describedherein include μ-opioid antagonists and δ-opioid receptor antagonists.Examples of useful opioid receptor antagonists include naloxone,naltrexone, methylnaltrexone, and nalmefene. Other useful opioidreceptor antagonists are known (see, e.g., Kreek et al., U.S. Pat. No.4,987,136).

Also provided are devices adapted for nasal delivery of a pharmaceuticalcomposition to a patient, comprising a therapeutically effective amountof an opioid antagonist, wherein the device is pre-primed, and whereinthe therapeutically effective amount is about 4 mg to about 12 mg. Insome embodiments, the therapeutically effective amount is equivalent toabout 3.4 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 4 mg of naloxonehydrochloride. In some embodiments, the opioid antagonist is selectedfrom naltrexone, methylnaltrexone, and nalmefene, and pharmaceuticallyacceptable salts thereof. In some embodiments, the opioid antagonist isnaltrexone hydrochloride. In some embodiments, the opioid antagonist ismethylnaltrexone bromide. In some embodiments, the opioid antagonist isnalmefene hydrochloride. In some embodiments, the opioid antagonist isthe only pharmaceutically active compound in pharmaceutical composition.

Nasal Drug Delivery Devices and Kits

Also provided are nasal drug delivery devices comprising apharmaceutical composition described herein. Nasal delivery isconsidered an attractive route for needle-free, systemic drug delivery,especially when rapid absorption and effect are desired. In addition,nasal delivery may help address issues related to poor bioavailability,slow absorption, drug degradation, and adverse events (AEs) in thegastrointestinal tract and avoids the first-pass metabolism in theliver.

Liquid nasal formulations are mainly aqueous solutions, but suspensionsand emulsions can also be delivered. In traditional spray pump systems,antimicrobial preservatives are typically required to maintainmicrobiological stability in liquid formulations.

Some EMS programs have developed a system using existing technologies ofan approved drug and an existing medical device to administer naloxoneintranasally, albeit in a non-FDA approved manner. This has beenaccomplished by using the injectable formulation (1 mg/mL) andadministering 1 mL per nostril via a marketed nasal atomizer/nebulizerdevice. The system combines an FDA-approved naloxone injection product(with a Luer fitted tip, no needles) with a marketed, medical devicecalled the Mucosal Atomization Device (MAD™ Nasal, Wolfe Tory Medical,Inc.). This initiative is consistent with the U.S. Needlestick Safetyand Prevention Act (Public Law 106-430). The EMS programs recognizelimitations of this system, one limitation being that it is notassembled and ready-to-use. Although this administration mode appears tobe effective in reversing narcosis, the formulation is not concentratedfor retention in the nasal cavity. The 1 mL delivery volume per nostrilis larger than that generally utilized for intranasal drugadministration. Therefore, there is loss of drug from the nasal cavity,due either to drainage into the nasopharynx or externally from the nasalcavity. The devices described herein are improved ready-to-use productsspecifically optimized, concentrated, and formulated for nasal delivery.

Metered spray pumps have dominated the nasal drug delivery market sincethey were introduced. The pumps typically deliver 100 μL (25-200 μL) perspray, and they offer high reproducibility of the emitted dose and plumegeometry in in vitro tests. The particle size and plume geometry canvary within certain limits and depend on the properties of the pump, theformulation, the orifice of the actuator, and the force applied.Traditional spray pumps replace the emitted liquid with air, andpreservatives are therefore required to prevent contamination. However,driven by the studies suggesting possible negative effects ofpreservatives, pump manufacturers have developed different spray systemsthat avoid the need for preservatives. These systems use a collapsiblebag, a movable piston, or a compressed gas to compensate for the emittedliquid volume (www.aptar.com and www.rexam.-com). The solutions with acollapsible bag and a movable piston compensating for the emitted liquidvolume offer the additional advantage that they can be emitted upsidedown, without the risk of sucking air into the dip tube and compromisingthe subsequent spray. This may be useful for some products where thepatients are bedridden and where a headdown application is recommended.Another method used for avoiding preservatives is that the air thatreplaces the emitted liquid is filtered through an aseptic air filter.In addition, some systems have a ball valve at the tip to preventcontamination of the liquid inside the applicator tip (www.aptar.com).More recently, pumps have been designed with side-actuation andintroduced for delivery of fluticasone furoate for the indication ofseasonal and perennial allergic rhinitis. The pump was designed with ashorter tip to avoid contact with the sensitive mucosal surfaces. Newdesigns to reduce the need for priming and re-priming, and pumpsincorporating pressure point features to improve the dosereproducibility and dose counters and lock-out mechanisms for enhanceddose control and safety are available (www.rexam.com and www.aptar.com).

Metered-dose spray pumps require priming and some degree of overfill tomaintain dose conformity for the labeled number of doses. They are wellsuited for drugs to be administered daily over a prolonged duration, butdue to the priming procedure and limited control of dosing, they areless suited for drugs with a narrow therapeutic window. For expensivedrugs and vaccines intended for single administration or sporadic useand where tight control of the dose and formulation is of particularimportance, single-dose or bi-dose spray devices are preferred(www.aptar.com). A simple variant of a single-dose spray device (MAD™)is offered by LMA (LMA, Salt Lake City, Utah, USA; www.lmana.com). Anosepiece with a spray tip is fitted to a standard syringe. The liquiddrug to be delivered is first drawn into the syringe and then the spraytip is fitted onto the syringe. This device has been used in academicstudies to deliver, for example, a topical steroid in patients withchronic rhinosinusitis and in a vaccine study. A pre-filled device basedon the same principle for one or two doses (Accuspray™, Becton DickinsonTechnologies, Research Triangle Park, N.C., USA; www.bdpharma.com) isused to deliver the influenza vaccine FluMist (www.flumist.com),approved for both adults and children in the US market. A similar devicefor two doses was marketed by a Swiss company for delivery of anotherinfluenza vaccine a decade ago. The single- and bi-dose devicesmentioned above consist of a reservoir, a piston, and a swirl chamber(see, e.g., the UDS UnitDose and BDS BiDose devices from Aptar, formerlyPfeiffer). The spray is formed when the liquid is forced out through theswirl chamber. These devices are held between the second and the thirdfingers with the thumb on the actuator. A pressure point mechanismincorporated in some devices secures reproducibility of the actuationforce and emitted plume characteristics. Currently, marketed nasalmigraine drugs like Imitrex (www.gsk.com) and Zomig (www.az.com;Pfeiffer/Aptar single-dose device) and the marketed influenza vaccineFlu-Mist (www.flumist.com; Becton Dickinson single-dose spray device)are delivered with this type of device.

With sterile filling, the use of preservatives is not required, butoverfill is required resulting in a waste fraction similar to themetered-dose, multi-dose sprays. To emit 100 μL, a volume of 125 μL isfilled in the device (Pfeiffer/Aptar single-dose device) used for theintranasal migraine medications Imitrex (sumatriptan) and Zomig(zolmitriptan) and about half of that for a bi-dose design. Sterile drugproducts may be produced using aseptic processing or terminalsterilization. Terminal sterilization usually involves filling andsealing product containers under high-quality environmental conditions.Products are filled and sealed in this type of environment to minimizethe microbial and particulate content of the in-process product and tohelp ensure that the subsequent sterilization process is successful. Inmost cases, the product, container, and closure have low bioburden, butthey are not sterile. The product in its final container is thensubjected to a sterilization process such as heat or irradiation. In anaseptic process, the drug product, container, and closure are firstsubjected to sterilization methods separately, as appropriate, and thenbrought together. Because there is no process to sterilize the productin its final container, it is critical that containers be filled andsealed in an extremely high-quality environment. Aseptic processinginvolves more variables than terminal sterilization. Before asepticassembly into a final product, the individual parts of the final productare generally subjected to various sterilization processes. For example,glass containers are subjected to dry heat; rubber closures aresubjected to moist heat; and liquid dosage forms are subjected tofiltration. Each of these manufacturing processes requires validationand control.

Accordingly, provided herein are devices adapted for nasal delivery of apharmaceutical composition to a patient, comprising a therapeuticallyeffective amount of an opioid antagonist selected from naloxone andpharmaceutically acceptable salts thereof, wherein said device ispre-primed, and wherein said therapeutically effective amount, isequivalent to about 2 mg to about 12 mg of naloxone hydrochloride.

In some embodiments, said opioid antagonist is naloxone hydrochloride.In some embodiments, said opioid antagonist is naloxone hydrochloridedihydrate.

In some embodiments, said patient is an opioid overdose patient or asuspected opioid overdose patient.

In some embodiments, said patient is in a lying, supine, or recoveryposition. In some embodiments, said patient is in a lying position. Insome embodiments, said patient is in a supine position. In someembodiments, said patient is in a recovery position.

In some embodiments, said therapeutically effective amount of an opioidantagonist is delivered by an untrained individual.

In some embodiments, said therapeutically effective amount is equivalentto about 4 mg to about 10 mg of naloxone hydrochloride. In someembodiments, said therapeutically effective amount is equivalent to anamount chosen from about 2 mg naloxone hydrochloride, about 4 mg ofnaloxone hydrochloride, and about 8 mg naloxone hydrochloride. In someembodiments, said therapeutically effective amount is equivalent toabout 2 mg of naloxone hydrochloride. In some embodiments, saidtherapeutically effective amount is equivalent to about 4 mg of naloxonehydrochloride. In some embodiments, said therapeutically effectiveamount is equivalent to about 8 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about3.4 mg of naloxone hydrochloride.

In some embodiments, said therapeutically effective amount is about 2.2mg to about 13.2 mg of naloxone hydrochloride dihydrate. In someembodiments, said therapeutically effective amount is about 4.4 mg toabout 11 mg of naloxone hydrochloride dihydrate. In some embodiments,said therapeutically effective amount is an amount chosen from about 2.2mg naloxone hydrochloride dihydrate, about 4.4 mg of naloxonehydrochloride dihydrate, and about 8.8 mg naloxone hydrochloridedihydrate. In some embodiments, said therapeutically effective amount isabout 2.2 mg of naloxone hydrochloride dihydrate. In some embodiments,said therapeutically effective amount is about 4.4 mg of naloxonehydrochloride dihydrate. In some embodiments, said therapeuticallyeffective amount is about 8.8 mg of naloxone hydrochloride dihydrate.

In some embodiments, said opioid antagonist is the only pharmaceuticallyactive compound in said pharmaceutical composition.

In some embodiments, said pharmaceutical composition comprises asolution of naloxone hydrochloride, or a hydrate thereof.

In some embodiments, the volume of said pharmaceutical composition insaid reservoir is not more than about 140 μL.

In some embodiments, about 100 μL of said pharmaceutical composition insaid reservoir is delivered to said patient in one actuation.

In some embodiments, said pharmaceutical composition further comprisesone or more excipients selected from water and NaCl.

In some embodiments, said pharmaceutical composition is substantiallyfree of antimicrobial preservatives.

In some embodiments, said pharmaceutical composition comprises acompound which is a preservative, cationic surfactant, and/orpermeation/penetration enhancer.

In certain embodiments, said pharmaceutical composition comprisesbenzalkonium chloride. The benzalkonium chloride can function as apreservative (even in low amounts), a permeation/penetration enhancer,and/or a cationic surfactant (typically at a higher amount for theselatter two). Benzalkonium chloride is represented by the followingstructure:

in which n is an integer, and a mixture of more than one thereof can beused. In certain embodiments, n is 8, 10, 12, 14, 16, or 18.

In some embodiments, said pharmaceutical composition further comprisesone or more excipients selected from water, NaCl, benzalkonium chloride,sodium edetate, disodium edetate, and hydrochloric acid.

In some embodiments, said pharmaceutical composition further compriseswater, NaCl, benzalkonium chloride, disodium edetate, and hydrochloricacid.

In some embodiments, said pharmaceutical composition further comprises:

-   -   an isotonicity agent;    -   a preservative;    -   a stabilizing agent;    -   an amount of an acid sufficient to achieve a pH or 3.5-5.5; and    -   an amount of water sufficient to achieve a final volume of about        100 μL.

In some embodiments, said pharmaceutical composition comprises:

-   -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   between about 0.005 mg and about 0.015 mg of a compound which is        a preservative, cationic surfactant, and/or permeation enhancer;    -   between about 0.1 mg and about 0.5 mg of a stabilizing agent;    -   an amount of an acid sufficient to achieve a pH or 3.5-5.5; and    -   an amount of water sufficient to achieve a final volume of about        100 μL.

In some embodiments,

-   -   the isotonicity agent is NaCl;    -   the compound which is a preservative, cationic surfactant,        and/or permeation enhancer is benzalkonium chloride;    -   the stabilizing agent is disodium edetate; and    -   the acid is hydrochloric acid.

In some embodiments, said pharmaceutical composition comprises:

-   -   about 0.74 mg NaCl;    -   about 0.01 mg benzalkonium chloride;    -   about 0.2 mg disodium edetate;    -   an amount of hydrochloric acid sufficient to achieve a pH or        3.5-5.5; and    -   an amount of water sufficient to achieve a final volume of about        100 μL.

In some embodiments, said device is filled with said pharmaceuticalcomposition using sterile filling.

In some embodiments, said pharmaceutical composition is storage-stablefor about twelve months at about 25° C. and about 60% relative humidity.

In some embodiments, said device is a single-dose device, wherein saidpharmaceutical composition is present in one reservoir, and wherein saidtherapeutically effective amount of said opioid antagonist is deliveredessentially by one actuation of said device into one nostril of saidpatient.

In some embodiments, about 100 μL of said pharmaceutical composition isdelivered by said actuation.

In some embodiments, said device is actuatable with one hand.

In some embodiments, the delivery time is less than about 25 seconds. Insome embodiments, the delivery time is less than about 20 seconds.

In some embodiments, the 90% confidence interval for dose delivered peractuation is ±about 2%. In some embodiments, the 95% confidence intervalfor dose delivered per actuation is ±about 2.5%.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 20% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally. In some embodiments, upon nasal delivery of saidpharmaceutical composition to said patient, less than about 10% of saidpharmaceutical composition leaves the nasal cavity via drainage into thenasopharynx or externally. In some embodiments, upon nasal delivery ofsaid pharmaceutical composition to said patient, less than about 5% ofsaid pharmaceutical composition leaves the nasal cavity via drainageinto the nasopharynx or externally.

In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a T_(max) of less than 30 minutes.In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a T_(max) of less than 25 minutes.In some embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a T_(max) of less than 20 minutes.In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a T_(max) of about 20 minutes. Insome embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a T_(max) of less than 19 minutes.In some embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a T_(max) of about 18.5 minutes.

In some embodiments, delivery of said therapeutically effective amountto said patient, provides occupancy at T_(max) of said opioid antagonistat the opioid receptors in the respiratory control center of saidpatient of greater than about 90%. In some embodiments, delivery of saidtherapeutically effective amount to said patient, provides occupancy atT_(max) of said opioid antagonist at the opioid receptors in therespiratory control center of said patient of greater than about 95%. Insome embodiments, delivery of said therapeutically effective amount tosaid patient, provides occupancy at T_(max) of said opioid antagonist atthe opioid receptors in the respiratory control center of said patientof greater than about 99%.

In some embodiments, said patient is free from respiratory depressionfor at least about 1 hour following treatment comprising essentially ofdelivery of said therapeutically effective amount of said opioidantagonist. In some embodiments, said patient is free from respiratorydepression for at least about 2 hours following treatment comprisingessentially of delivery of said therapeutically effective amount of saidopioid antagonist. In some embodiments, said patient is free fromrespiratory depression for at least about 4 hours following treatmentcomprising essentially of delivery of said therapeutically effectiveamount of said opioid antagonist. In some embodiments, said patient isfree from respiratory depression for at least about 6 hours followingtreatment comprising essentially of delivery of said therapeuticallyeffective amount of said opioid antagonist.

In some embodiments, said device is a bi-dose device, wherein a firstvolume of said pharmaceutical composition is present in a firstreservoir and a second volume of said pharmaceutical composition ispresent in a second reservoir, and wherein said therapeuticallyeffective amount is delivered essentially by a first actuation of saiddevice into a first nostril of said patient and a second actuation ofsaid device into a second nostril of said patient.

In some embodiments, said first volume and said second volume combinedis equal to not more than about 380 μL.

In some embodiments, about 100 μL of said first volume of saidpharmaceutical composition is delivered by said first actuation.

In some embodiments, about 100 μL of said second volume of saidpharmaceutical composition is delivered by said second actuation.

In some embodiments, said device is actuatable with one hand.

In some embodiments, the delivery time is less than about 25 seconds. Insome embodiments, the delivery time is less than about 20 seconds.

In some embodiments, the 90% confidence interval for dose delivered peractuation is ±about 2%. In some embodiments, the 95% confidence intervalfor dose delivered per actuation is ±about 2.5%.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 20% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally. In some embodiments, upon nasal delivery of saidpharmaceutical composition to said patient, less than about 10% of saidpharmaceutical composition leaves the nasal cavity via drainage into thenasopharynx or externally. In some embodiments, upon nasal delivery ofsaid pharmaceutical composition to said patient, less than about 5% ofsaid pharmaceutical composition leaves the nasal cavity via drainageinto the nasopharynx or externally.

In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a T_(max) of less than 30 minutes.In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a T_(max) of less than 25 minutes.In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a T_(max) of about 20 minutes. Insome embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a T_(max) of less than 19 minutes.In some embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a T_(max) of about 18.5 minutes.

In some embodiments, delivery of said therapeutically effective amountto said patient, provides occupancy at T_(max) of said opioid antagonistat the opioid receptors in the respiratory control center of saidpatient of greater than about 90%. In some embodiments, delivery of saidtherapeutically effective amount to said patient, provides occupancy atT_(max) of said opioid antagonist at the opioid receptors in therespiratory control center of said patient of greater than about 95%. Insome embodiments, delivery of said therapeutically effective amount tosaid patient, provides occupancy at T_(max) of said opioid antagonist atthe opioid receptors in the respiratory control center of said patientof greater than about 99%.

In some embodiments, said patient is free from respiratory depressionfor at least about 1 hour following treatment comprising essentially ofdelivery of said therapeutically effective amount of said opioidantagonist. In some embodiments, said patient is free from respiratorydepression for at least about 2 hours following treatment comprisingessentially of delivery of said therapeutically effective amount of saidopioid antagonist. In some embodiments, said patient is free fromrespiratory depression for at least about 4 hours following treatmentcomprising essentially of delivery of said therapeutically effectiveamount of said opioid antagonist. In some embodiments, said patient isfree from respiratory depression for at least about 6 hours followingtreatment comprising essentially of delivery of said therapeuticallyeffective amount of said opioid antagonist.

Also provided herein is a single-use, pre-primed device adapted fornasal delivery of a pharmaceutical composition to a patient by oneactuation of said device into one nostril of said patient, having asingle reservoir comprising about 100 μL of a pharmaceutical compositionwhich is an aqueous solution comprising:

-   -   about 2 mg or about 4 mg naloxone hydrochloride or a hydrate        thereof,    -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   between about 0.005 mg and about 0.015 mg of a compound which is        a preservative, cationic surfactant, and/or permeation enhancer;    -   between about 0.1 mg and about 0.5 mg of a stabilizing agent;    -   an amount of an acid sufficient to achieve a pH or 3.5-5.5.

In some embodiments, the device comprises about 4 mg naloxonehydrochloride or a hydrate thereof. In some embodiments, the devicecomprises about 2 mg naloxone hydrochloride or a hydrate thereof. Insome embodiments, the device comprises about 4.4 mg naloxonehydrochloride dihydrate. In some embodiments, the device comprises about2.2 mg naloxone hydrochloride dihydrate.

In some embodiments,

-   -   the isotonicity agent is NaCl;    -   the compound which is a preservative, cationic surfactant,        and/or permeation enhancer is benzalkonium chloride;    -   the stabilizing agent is disodium edetate; and    -   the acid is hydrochloric acid.

In some embodiments, the device comprises:

-   -   about 2.2 mg or about 4.4 mg naloxone hydrochloride dihydrate;    -   about 0.74 mg NaCl;    -   about 0.01 mg benzalkonium chloride;    -   about 0.2 mg disodium edetate; and    -   an amount of hydrochloric acid sufficient to achieve a pH or        3.5-5.5.

In some embodiments, the device comprises about 4.4 mg naloxonehydrochloride dihydrate. In some embodiments, the device comprises about2.2 mg naloxone hydrochloride dihydrate.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 10% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally.

In some embodiments, the plasma concentration versus time curve of saidnaloxone hydrochloride in said patient has a T_(max) of between about 20and about 30 minutes.

In some embodiments, said device is actuatable with one hand.

In some embodiments, the delivery time is less than about 25 seconds. Insome embodiments, the delivery time is less than about 20 seconds.

In some embodiments, the 90% confidence interval for dose delivered peractuation is ±about 2%. In some embodiments, the 95% confidence intervalfor dose delivered per actuation is ±about 2.5%.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 20% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally. In some embodiments, upon nasal delivery of saidpharmaceutical composition to said patient, less than about 10% of saidpharmaceutical composition leaves the nasal cavity via drainage into thenasopharynx or externally. In some embodiments, upon nasal delivery ofsaid pharmaceutical composition to said patient, less than about 5% ofsaid pharmaceutical composition leaves the nasal cavity via drainageinto the nasopharynx or externally.

In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a T_(max) of less than 30 minutes.In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a T_(max) of less than 25 minutes.In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a T_(max) of about 20 minutes. Insome embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a T_(max) of less than 19 minutes.In some embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a T_(max) of about 18.5 minutes.

In some embodiments, delivery of said therapeutically effective amountto said patient, provides occupancy at T_(max) of said opioid antagonistat the opioid receptors in the respiratory control center of saidpatient of greater than about 90%. In some embodiments, delivery of saidtherapeutically effective amount to said patient, provides occupancy atT_(max) of said opioid antagonist at the opioid receptors in therespiratory control center of said patient of greater than about 95%. Insome embodiments, delivery of said therapeutically effective amount tosaid patient, provides occupancy at T_(max) of said opioid antagonist atthe opioid receptors in the respiratory control center of said patientof greater than about 99%.

In some embodiments, said patient is free from respiratory depressionfor at least about 1 hour following treatment comprising essentially ofdelivery of said therapeutically effective amount of said opioidantagonist. In some embodiments, said patient is free from respiratorydepression for at least about 2 hours following treatment comprisingessentially of delivery of said therapeutically effective amount of saidopioid antagonist. In some embodiments, said patient is free fromrespiratory depression for at least about 4 hours following treatmentcomprising essentially of delivery of said therapeutically effectiveamount of said opioid antagonist. In some embodiments, said patient isfree from respiratory depression for at least about 6 hours followingtreatment comprising essentially of delivery of said therapeuticallyeffective amount of said opioid antagonist.

In some embodiments, said device is filled with said pharmaceuticalcomposition using sterile filling.

In some embodiments, said pharmaceutical composition is storage-stablefor about twelve months at about 25° C. and about 60% relative humidity.

In some embodiments, said opioid antagonist is the only pharmaceuticallyactive compound in said pharmaceutical composition.

Also provided are devices as recited in any of the preceding embodimentsfor use in the treatment of an opioid overdose symptom selected from:respiratory depression, postoperative opioid respiratory depression,altered level consciousness, miotic pupils, cardiovascular depression,hypoxemia, acute lung injury, aspiration pneumonia, sedation, andhypotension.

Also provided are devices as recited in any of the preceding embodimentsfor use in the reversal of respiratory depression induced by opioids.

In some embodiments, said respiratory depression is caused by theillicit use of opioids or by an accidental misuse of opioids duringmedical opioid therapy.

Also provided are devices as recited in any of the preceding embodimentsfor use in the complete or partial reversal of narcotic depression,including respiratory depression, induced by opioids selected from:natural and synthetic narcotics, propoxyphene, methadone, nalbuphine,pentazocine and butorphanol.

In some embodiments, said patient is an opioid overdose patient or asuspected opioid overdose patient.

In some embodiments, said patient is in a lying, supine, or recoveryposition. In some embodiments, said patient is in a lying position. Insome embodiments, said patient is in a supine position. In someembodiments, said patient is in a recovery position.

In some embodiments, said therapeutically effective amount of an opioidantagonist is delivered by an untrained individual.

Also provided are kits comprising a device described herein and writteninstructions for using the device. Also provided are kits comprising adevice described herein and an opioid agonist. In some embodiments thekit further comprises written instructions. In some embodiments, theopioid agonist is selected from codeine, morphine, methadone, fentanyl,oxycodone HCl, hydrocodone bitartrate, hydromorphone, oxymorphone,meperidine, propoxyphene, opium, heroin, and certain narcotic-antagonistanalgesics, such as, nalbuphine, pentazocine and butorphanol. In someembodiments, the opioid agonist is selected from tapentadol andtramadol.

Also provided are embodiments wherein any embodiment above in paragraphs[087]-[0153] above may be combined with any one or more of theseembodiments, provided the combination is not mutually exclusive.

Tamper-proof and tamper-resistant formulating technologies have beendeveloped for safer delivery of opioid antagonists, but suchformulations are still abused resulting in opioid overdose. One suchtechnology (Abuse Deterrent Prolonged Release Erosion Matrix (ADPREM);Egalet) utilizes a water-degradable polymer matrix technology thaterodes from the surface at a constant rate. The matrix consists of oneor more plasticizing polymers that cannot be crushed or melted. Anothersuch technology (Abuse Resistant Technology (ART); Elite Laboratories)utilizes a proprietary coating technology consisting of various polymersthat can sequester an opioid antagonist (naltrexone) in fragilemicropellets that are indistinguishable from the pellets containing theopioid. The formulation is designed to release sequestered antagonistonly if the dosage is crushed or otherwise damaged for extraction. Oraldosage forms are prepared by coating powders, crystals, granules, orpellets with various polymers to impart different characteristics. Theformulations can release the active drug in both immediate and sustainedrelease form. Chronodelivery formulations using this technology caneffectively delay drug absorption for up to five hours. Aversion (AcuraPharmaceuticals) utilizes certain proprietary combinations of functionalexcipients (e.g., gelling agents) and active ingredients intended todiscourage the most common methods of prescription drug misuse andabuse. Ingredients may include nasal irritants (e.g., capsaicin) andaversive agents (e.g., niacin). In some embodiments, the opioid agonistis in a tamper-proof formulation. In some embodiments, the opioidagonist is in a tamper-resistant formulation. In some embodiments, theopioid agonist is selected from Acurox® Oxycodone DETERx®, Egalethydrocodone, Egalet morphine, Egalet oxycodone, Exalgo®, Opana®, andRemoxy®.

Pharmaceutical Compositions

Also provided are pharmaceutical compositions comprising one or moreopioid antagonist. In some embodiments the pharmaceutical compositionscomprise an opioid antagonist and a pharmaceutically acceptable carrier.The carrier(s) must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation and not overly deleteriousto the recipient thereof. Some embodiments of the present inventioninclude a method of producing a pharmaceutical composition comprisingadmixing at least one opioid antagonist and a pharmaceuticallyacceptable carrier. Pharmaceutical compositions are applied directly tothe nasal cavity using the devices described herein. In the case of aspray, this may be achieved for example by means of a metering atomizingspray pump.

Liquid preparations include solutions, suspensions and emulsions, forexample, water or water-propylene glycol solutions. Additionalingredients in liquid preparations may include: antimicrobialpreservatives, such as benzalkonium chloride (which may also act as acationic surfactant and/or a permeation enhancer), methylparaben, sodiumbenzoate, benzoic acid, phenyl ethyl alcohol, and the like, and mixturesthereof, surfactants such as Polysorbate 80 NF, polyoxyethylene 20sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate,polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitanmonostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene20 sorbitan tristearate, polyoxyethylene (5) sorbitan monooleate,polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitanmonoisostearate, sorbitan monooleate, sorbitan monolaurate, sorbitanmonopalmitate, sorbitan monostearate, sorbitan trilaurate, sorbitantrioleate, sorbitan tristearate, and the like, and mixtures thereof; atonicity agent such as: dextrose, lactose, sodium chloride, calciumchloride, magnesium chloride, sorbitol, sucrose, mannitol, trehalose,raffinose, polyethylene glycol, hydroxyethyl starch, glycine, and thelike, and mixtures thereof, and a suspending agent such asmicrocrystalline cellulose, carboxymethylcellulose sodium NF,polyacrylic acid, magnesium aluminum silicate, xanthan gum, and thelike, and mixtures thereof.

The opioid antagonists described herein can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington: TheScience and Practice of Pharmacy, 21st ed., Lippincott Williams &Wilkins, Philadelphia, Pa. (2005).

The opioid antagonists described herein may optionally exist aspharmaceutically acceptable salts including pharmaceutically acceptableacid addition salts prepared from pharmaceutically acceptable non-toxicacids including inorganic and organic acids. Representative acidsinclude, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric,tartaric, oxalic, p-toluenesulfonic and the like, such as thosepharmaceutically acceptable salts listed by Berge et al., Journal ofPharmaceutical Sciences, 66:1-19 (1977). The acid addition salts may beobtained as the direct products of compound synthesis. In thealternative, the free base may be dissolved in a suitable solventcontaining the appropriate acid and the salt isolated by evaporating thesolvent or otherwise separating the salt and solvent. The opioidantagonists described herein may form solvates with standard lowmolecular weight solvents using methods known to the skilled artisan.

Accordingly, provided herein are pharmaceutical formulations forintranasal administration comprising, in an aqueous solution of not morethan about 140 μL: between about 2 mg and about 12 mg of an opioidantagonist;

-   -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   between about 0.005 mg and about 0.015 mg of a compound which is        a preservative, cationic surfactant, and/or permeation enhancer;    -   between about 0.1 mg and about 0.5 mg of a stabilizing agent;    -   an amount of an acid sufficient to achieve a pH or 3.5-5.5.

In some embodiments, said opioid antagonist is the only pharmaceuticallyactive compound in said pharmaceutical composition.

In some embodiments, said opioid antagonist is naloxone hydrochloride,or a hydrate thereof.

In some embodiments, said opioid antagonist is naloxone hydrochloridedihydrate.

In some embodiments, the pharmaceutical formulation comprises an amountequivalent to about 4 mg to about 10 mg of naloxone hydrochloride. Insome embodiments, the pharmaceutical formulation comprises an amountequivalent to an amount chosen from about 2 mg naloxone hydrochloride,about 4 mg of naloxone hydrochloride, and about 8 mg naloxonehydrochloride. In some embodiments, the pharmaceutical formulationcomprises an amount equivalent to about 2 mg of naloxone hydrochloride.In some embodiments, the pharmaceutical formulation comprises an amountequivalent to about 4 mg of naloxone hydrochloride. In some embodiments,the pharmaceutical formulation comprises an amount equivalent to about 8mg of naloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 3.4 mg of naloxonehydrochloride.

In some embodiments, the pharmaceutical formulation comprises about 2.2mg to about 13.2 mg of naloxone hydrochloride dihydrate. In someembodiments, the pharmaceutical formulation comprises about 4.4 mg toabout 11 mg of naloxone hydrochloride dihydrate. In some embodiments,the pharmaceutical formulation comprises an amount chosen from about 2.2mg naloxone hydrochloride dihydrate, about 4.4 mg of naloxonehydrochloride dihydrate, and about 8.8 mg naloxone hydrochloridedihydrate. In some embodiments, the pharmaceutical formulation comprisesabout 2.2 mg of naloxone hydrochloride dihydrate. In some embodiments,the pharmaceutical formulation comprises about 4.4 mg of naloxonehydrochloride dihydrate. In some embodiments, the pharmaceuticalformulation comprises about 8.8 mg of naloxone hydrochloride dihydrate.

In some embodiments, the device comprises about 4.4 mg naloxonehydrochloride dihydrate. In some embodiments, the device comprises about2.2 mg naloxone hydrochloride dihydrate.

In some embodiments, the pharmaceutical composition is in an aqueoussolution of about 100 μL

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 10% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally.

In some embodiments, the plasma concentration versus time curve of saidnaloxone hydrochloride in said patient has a T_(max) of between about 20and about 30 minutes.

In some embodiments, said device is actuatable with one hand.

In some embodiments, the delivery time is less than about 25 seconds. Insome embodiments, the delivery time is less than about 20 seconds.

In some embodiments, the 90% confidence interval for dose delivered peractuation is ±about 2%. In some embodiments, the 95% confidence intervalfor dose delivered per actuation is ±about 2.5%.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 20% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally. In some embodiments, upon nasal delivery of saidpharmaceutical composition to said patient, less than about 10% of saidpharmaceutical composition leaves the nasal cavity via drainage into thenasopharynx or externally. In some embodiments, upon nasal delivery ofsaid pharmaceutical composition to said patient, less than about 5% ofsaid pharmaceutical composition leaves the nasal cavity via drainageinto the nasopharynx or externally.

In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in a patient has a T_(max) of less than 30 minutes. Insome embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a T_(max) of less than 25 minutes.In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a T_(max) of about 20 minutes. Insome embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a T_(max) of less than 19 minutes.In some embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a T_(max) of about 18.5 minutes.

In some embodiments, delivery of said pharmaceutical formulation to apatient, provides occupancy at T_(max) of said opioid antagonist at theopioid receptors in the respiratory control center of said patient ofgreater than about 90%. In some embodiments, delivery of saidpharmaceutical formulation to said patient, provides occupancy atT_(max) of said opioid antagonist at the opioid receptors in therespiratory control center of said patient of greater than about 95%. Insome embodiments, delivery of said pharmaceutical formulation to saidpatient, provides occupancy at T_(max) of said opioid antagonist at theopioid receptors in the respiratory control center of said patient ofgreater than about 99%.

In some embodiments, said patient is free from respiratory depressionfor at least about 1 hour following treatment comprising essentially ofdelivery of said therapeutically effective amount of said opioidantagonist. In some embodiments, said patient is free from respiratorydepression for at least about 2 hours following treatment comprisingessentially of delivery of said therapeutically effective amount of saidopioid antagonist. In some embodiments, said patient is free fromrespiratory depression for at least about 4 hours following treatmentcomprising essentially of delivery of said therapeutically effectiveamount of said opioid antagonist. In some embodiments, said patient isfree from respiratory depression for at least about 6 hours followingtreatment comprising essentially of delivery of said therapeuticallyeffective amount of said opioid antagonist.

Also provided herein are pharmaceutical formulations for intranasaladministration comprising, in an aqueous solution of not more than about140 μL:

-   -   about 2 mg or about 4 mg naloxone hydrochloride or a hydrate        thereof;    -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   between about 0.005 mg and about 0.015 mg of a compound which is        a preservative, cationic surfactant, and/or permeation enhancer;    -   between about 0.1 mg and about 0.5 mg of a stabilizing agent;    -   an amount of hydrochloric acid sufficient to achieve a pH or        3.5-5.5.

In some embodiments,

-   -   the isotonicity agent is NaCl;    -   the compound which is a preservative, cationic surfactant,        and/or permeation enhancer is benzalkonium chloride;    -   the stabilizing agent is disodium edetate; and    -   the acid is hydrochloric acid.

In some embodiments, the pharmaceutical formulation comprises:

-   -   about 2.2 mg or about 4.4 mg naloxone hydrochloride dihydrate;    -   about 0.74 mg NaCl;    -   about 0.01 mg benzalkonium chloride;    -   about 0.2 mg disodium edetate; and    -   an amount of hydrochloric acid sufficient to achieve a pH or        3.5-5.5.

In some embodiments, the pharmaceutical formulation comprises about 4 mgnaloxone hydrochloride or a hydrate thereof. In some embodiments, thepharmaceutical formulation comprises about 2 mg naloxone hydrochlorideor a hydrate thereof. In some embodiments, the pharmaceuticalformulation comprises about 4.4 mg naloxone hydrochloride dihydrate. Insome embodiments, the pharmaceutical formulation comprises about 2.2 mgnaloxone hydrochloride dihydrate.

Also provided herein are pharmaceutical formulations for intranasaladministration comprising, in an aqueous solution of about 100 μL:

-   -   about 4 mg naloxone hydrochloride or a hydrate thereof;    -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   between about 0.005 mg and about 0.015 mg of a compound which is        a preservative, cationic surfactant, and/or permeation enhancer;    -   between about 0.1 mg and about 0.5 mg of a stabilizing agent;    -   an amount of an acid sufficient to achieve a pH or 3.5-5.5.

In some embodiments, the pharmaceutical formulation comprises:

-   -   about 4.4 mg naloxone hydrochloride dihydrate;    -   about 0.74 mg NaCl;    -   about 0.01 mg benzalkonium chloride;    -   about 0.2 mg disodium edetate; and    -   an amount of hydrochloric acid sufficient to achieve a pH or        3.5-5.5.

Also provided herein are pharmaceutical formulations for intranasaladministration comprising, in an aqueous solution of about 100 μL:

-   -   about 2 mg naloxone hydrochloride or a hydrate thereof;    -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   between about 0.005 mg and about 0.015 mg of a compound which is        a preservative, cationic surfactant, and/or permeation enhancer;    -   between about 0.1 mg and about 0.5 mg of a stabilizing agent;    -   an amount of an acid sufficient to achieve a pH or 3.5-5.5.

In some embodiments, the pharmaceutical formulation comprises:

-   -   about 2.2 mg naloxone hydrochloride dihydrate;    -   about 0.74 mg NaCl;    -   about 0.01 mg benzalkonium chloride;    -   about 0.2 mg disodium edetate; and    -   an amount of hydrochloric acid sufficient to achieve a pH or        3.5-5.5.

In some embodiments, the pharmaceutical formulation comprises about 4.4mg naloxone hydrochloride dihydrate. In some embodiments, thepharmaceutical formulation comprises about 2.2 mg naloxone hydrochloridedihydrate.

Provided are devices adapted for nasal delivery of a pharmaceuticalcomposition to a patient, comprising a therapeutically effective amountof an opioid antagonist selected from naloxone and pharmaceuticallyacceptable salts thereof, wherein the device is pre-primed, and whereinthe therapeutically effective amount, is equivalent to about 2 mg toabout 12 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 4.4 mg ofnaloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 4.4 mg of naloxonehydrochloride. In some embodiments, the pharmaceutical compositioncomprises a solution of naloxone hydrochloride dihydrate. In someembodiments, the pharmaceutical composition further comprises one ormore excipients selected from water and NaCl. In some embodiments, thepharmaceutical composition is substantially free of antimicrobialpreservatives. In some embodiments, the device is substantially free ofbenzalkonium chloride, methylparaben, sodium benzoate, benzoic acid,phenyl ethyl alcohol In some embodiments, the device is filled with thepharmaceutical composition in a sterile environment. In someembodiments, the pharmaceutical composition is storage-stable for abouttwelve months at about 25° C. In some embodiments, the pharmaceuticalcomposition comprises less than 0.1% w/w antimicrobial preservatives. Insome embodiments, the pharmaceutical composition comprises 0.01% w/w orless antimicrobial preservatives. In some embodiments, thepharmaceutical composition comprises 0.01% w/w-0.001% w/w antimicrobialpreservatives. In some embodiments, the pharmaceutical compositioncomprises less than 0.001% w/w antimicrobial preservatives.

Also provided are devices for “combination-therapy” comprisingpharmaceutical compositions comprising at least one opioid antagonistdescribed herein, together with at least one known pharmaceutical agentand a pharmaceutically acceptable carrier. In some embodiments, thepharmaceutical composition comprises a short-acting opioid antagonistand a long-acting opioid antagonist. In some embodiments, thepharmaceutical composition comprises naloxone and naltrexone. In someembodiments, the pharmaceutical composition comprises naloxone andmethylnaltrexone. In some embodiments, the pharmaceutical compositioncomprises naloxone and nalmefene.

Also provided are embodiments wherein any embodiment above in paragraphs[0159]-[0185] above may be combined with any one or more of theseembodiments, provided the combination is not mutually exclusive.

Indications

Also provided are devices for use in treating opioid overdose andsymptoms thereof and methods of using the devices. Naloxone prevents orreverses the effects of opioids including respiratory depression,sedation and hypotension. Also, it can reverse the psychotomimetic anddysphoric effects of agonist-antagonists such as pentazocine. Naloxonecauses abrupt reversal of narcotic depression which may result innausea, vomiting, sweating, tachycardia, increased blood pressure,tremulousness, seizures and cardiac arrest, however, there is noclinical experience with naloxone hydrochloride overdosage in humans. Inthe mouse and rat the intravenous LD50 is 150±5 mg/kg and 109±4 mg/kgrespectively. In acute subcutaneous toxicity studies in newborn rats theLD50 (95% CL) is 260 (228-296) mg/kg. Subcutaneous injection of 100mg/kg/day in rats for 3 weeks produced only transient salivation andpartial ptosis following injection: no toxic effects were seen at 10mg/kg/day for 3 weeks.

Naloxone hydrochloride injection is indicated for the complete orpartial reversal of narcotic depression, including respiratorydepression, induced by opioids selected from: natural and syntheticnarcotics, propoxyphene, methadone, and certain narcotic-antagonistanalgesics: nalbuphine, pentazocine and butorphanol. Naloxonehydrochloride is also indicated for the diagnosis of suspected acuteopioid overdosage. For the treatment of known or suspected narcoticoverdose in adults an initial dose of 0.4 mg to 2 mg of naloxonehydrochloride intravenously is indicated. If the desired degree ofcounteraction and improvement in respiratory functions is not obtained,administration may be repeated at 2 to 3 minute intervals. If noresponse is observed after 10 mg of naloxone hydrochloride have beenadministered, the diagnosis of narcotic-induced or partialnarcotic-induced toxicity should be questioned. The usual initial dosein children is 0.01 mg/kg body weight given IV. If this dose does notresult in the desired degree of clinical improvement, a subsequent doseof 0.1 mg/kg body weight may be administered. When using naloxonehydrochloride injection in neonates a product containing 0.02 mg/mLshould be used.

It has also been reported that naloxone hydrochloride is an effectiveagent for the reversal of the cardiovascular and respiratory depressionassociated with narcotic and possibly some non-narcotic overdoses. Theauthors stated that due to naloxone's pharmacokinetic profile, acontinuous infusion protocol is recommended when prolonged narcoticantagonist effects are required. (Handal et al., Ann Emerg Med. 1983July; 12(7):438-45).

Accordingly, also provided herein are methods of treating opioidoverdose or a symptom thereof, comprising nasally administering to apatient in need thereof a therapeutically effective amount of an opioidantagonist selected from naloxone and pharmaceutically acceptable saltsthereof, wherein said therapeutically effective amount is equivalent toabout 2 mg to about 12 mg of naloxone hydrochloride or a hydratethereof. In some embodiments, the therapeutically effective amount of anopioid antagonist selected from naloxone and pharmaceutically acceptablesalts thereof is delivered in not more than about 140 μL of an aqueouscarrier solution.

In certain embodiments, also provided herein are methods of treatingopioid overdose or a symptom thereof, comprising nasally administeringto a patient in need thereof a therapeutically effective amount of anopioid antagonist selected from naloxone and pharmaceutically acceptablesalts thereof, wherein said therapeutically effective amount isequivalent to about 2 mg to about 12 mg of naloxone hydrochloride or ahydrate thereof in not more than about 140 μL of an aqueous carriersolution.

In certain embodiments, also provided herein are methods of treatingopioid overdose or a symptom thereof, comprising nasally administeringto a patient in need thereof a single dose of a therapeuticallyeffective amount of an opioid antagonist selected from naloxone andpharmaceutically acceptable salts thereof, wherein said therapeuticallyeffective amount is equivalent to about 2 mg to about 12 mg of naloxonehydrochloride or a hydrate thereof in not more than about 140 μL of anaqueous carrier solution.

In some embodiments, said opioid antagonist is the only pharmaceuticallyactive compound in said pharmaceutical composition.

In some embodiments, said opioid antagonist is naloxone hydrochloride.In some embodiments, said opioid antagonist is naloxone hydrochloridedihydrate.

In some embodiments, said pharmaceutical composition comprises asolution of naloxone hydrochloride, or a hydrate thereof.

In some embodiments, said patient is an opioid overdose patient or asuspected opioid overdose patient.

In some embodiments, said patient is in a lying, supine, or recoveryposition. In some embodiments, said patient is in a lying position. Insome embodiments, said patient is in a supine position. In someembodiments, said patient is in a recovery position.

In some embodiments, said therapeutically effective amount of an opioidantagonist is delivered by an untrained individual.

In some embodiments, said therapeutically effective amount is equivalentto about 4 mg to about 10 mg of naloxone hydrochloride. In someembodiments, said therapeutically effective amount is equivalent to anamount chosen from about 2 mg naloxone hydrochloride, about 4 mg ofnaloxone hydrochloride, and about 8 mg naloxone hydrochloride. In someembodiments, said therapeutically effective amount is equivalent toabout 2 mg of naloxone hydrochloride. In some embodiments, saidtherapeutically effective amount is equivalent to about 4 mg of naloxonehydrochloride. In some embodiments, said therapeutically effectiveamount is equivalent to about 8 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about3.4 mg of naloxone hydrochloride.

In some embodiments, said therapeutically effective amount is about 2.2mg to about 13.2 mg of naloxone hydrochloride dihydrate. In someembodiments, said therapeutically effective amount is about 4.4 mg toabout 11 mg of naloxone hydrochloride dihydrate. In some embodiments,said therapeutically effective amount is an amount chosen from about 2.2mg naloxone hydrochloride dihydrate, about 4.4 mg of naloxonehydrochloride dihydrate, and about 8.8 mg naloxone hydrochloridedihydrate. In some embodiments, said therapeutically effective amount isabout 2.2 mg of naloxone hydrochloride dihydrate. In some embodiments,said therapeutically effective amount is about 4.4 mg of naloxonehydrochloride dihydrate. In some embodiments, said therapeuticallyeffective amount is about 8.8 mg of naloxone hydrochloride dihydrate.

In some embodiments, said symptom is chosen from respiratory depressionand central nervous system depression.

In some embodiments, said patient exhibits any of unresponsiveness tostimulus, unconsciousness, stopped breathing; erratic or stopped pulse,choking or gurgling sounds, blue or purple fingernails or lips, slack orlimp muscle tone, contracted pupils, and vomiting.

In some embodiments, said patient is not breathing.

In some embodiments, said patient is in a lying, supine, or recoveryposition.

In some embodiments, said patient is in a lying position.

In some embodiments, said patient is in a supine position.

In some embodiments, said patient is a recovery position.

In some embodiments, said therapeutically effective amount is equivalentto about 2 mg to about 10 mg of naloxone hydrochloride.

In some embodiments, said therapeutically effective amount is equivalentto an amount chosen from about 2 mg naloxone hydrochloride, about 4 mgof naloxone hydrochloride, and about 8 mg naloxone hydrochloride.

In some embodiments, said therapeutically effective amount is equivalentto about 2 mg of naloxone hydrochloride.

In some embodiments, said therapeutically effective amount is equivalentto about 4 mg of naloxone hydrochloride.

In some embodiments, said therapeutically effective amount is equivalentto about 8 mg of naloxone hydrochloride.

In some embodiments, said opioid antagonist is the only pharmaceuticallyactive compound in said pharmaceutical composition.

In some embodiments, said opioid antagonist is naloxone hydrochloride.

In some embodiments, said nasally administering is accomplished using apre-primed device adapted for nasal delivery of a pharmaceuticalcomposition.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 20% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 10% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 5% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally.

In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a T_(max) of less than 30 minutes.

In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a T_(max) of less than 25 minutes.

In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a T_(max) of about 20 minutes.

In some embodiments, said opioid overdose symptom is selected from:respiratory depression, central nervous system depression, andcardiovascular depression.

In some embodiments, said opioid overdose symptom is respiratorydepression induced by opioids.

In some embodiments, said respiratory depression is caused by theillicit use of opioids or by an accidental misuse of opioids duringmedical opioid therapy.

In some embodiments, said respiratory depression is induced by opioidsselected from: natural and synthetic narcotics, propoxyphene, methadone,nalbuphine, pentazocine and butorphanol.

In some embodiments, said respiratory depression is induced by an opioidselected from codeine, morphine, methadone, fentanyl, oxycodone HCl,hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine,propoxyphene, opium, heroin, tramadol, tapentadol.

In some embodiments, said patient is free from respiratory depressionfor at least about 1 hour following treatment comprising essentially ofdelivery of said therapeutically effective amount of said opioidantagonist.

In some embodiments, said patient is free from respiratory depressionfor at least about 2 hours following treatment comprising essentially ofdelivery of said therapeutically effective amount of said opioidantagonist.

In some embodiments, said patient is free from respiratory depressionfor at least about 4 hours following treatment comprising essentially ofdelivery of said therapeutically effective amount of said opioidantagonist.

In some embodiments, said patient is free from respiratory depressionfor at least about 6 hours following treatment comprising essentially ofdelivery of said therapeutically effective amount of said opioidantagonist.

Also provided are embodiments wherein any embodiment above in paragraphs[0188]-[0228] above may be combined with any one or more of theseembodiments, provided the combination is not mutually exclusive.

Also provided are the devices, pharmaceutical compositions, kits, andmethods of treatment described herein for use in the treatment of anopioid overdose symptom selected from: respiratory depression,postoperative opioid respiratory depression, altered levelconsciousness, miotic pupils, cardiovascular depression, hypoxemia,acute lung injury, aspiration pneumonia, sedation, and hypotension. Alsoprovided are the devices, pharmaceutical compositions, kits, and methodsof treatment described herein for use in the reversal of respiratorydepression induced by opioids. In some embodiments, the respiratorydepression is caused by the illicit use of opioids or by an accidentalmisuse of opioids during medical opioid therapy. Also provided are thedevices, pharmaceutical compositions, kits, and methods of treatmentdescribed herein for use in the complete or partial reversal of narcoticdepression, including respiratory depression, induced by opioidsselected from: natural and synthetic narcotics, propoxyphene, methadone,nalbuphine, pentazocine and butorphanol. In some embodiments, narcoticdepression, including respiratory depression, is induced by an opioidagonist selected from codeine, morphine, methadone, fentanyl, oxycodoneHCl, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine,propoxyphene, opium, heroin, tramadol, and tapentadol.

Also provided are devices, pharmaceutical formulations, and kits for,and methods of, treating opioid overdose or a symptom thereof,comprising nasally administering to a patient in need thereof atherapeutically effective amount of an opioid antagonist selected fromnaloxone and pharmaceutically acceptable salts thereof, wherein thetherapeutically effective amount is equivalent to about 2 mg to about 12mg of naloxone hydrochloride. In some embodiments, the patient is notbreathing. Also provided are devices adapted for nasal delivery of apharmaceutical composition to a patient, comprising a therapeuticallyeffective amount of an opioid antagonist selected from naloxone andpharmaceutically acceptable salts thereof, wherein the device ispre-primed, and wherein the therapeutically effective amount, isequivalent to about 4 mg to about 12 mg of naloxone hydrochloride. Insome embodiments, the therapeutically effective amount is equivalent toabout 2 mg to about 24 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about3 mg to about 18 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 4 mg to about 10mg of naloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 5 mg to about 11 mg of naloxonehydrochloride. In some embodiments, the therapeutically effective amountis equivalent to about 6 mg to about 10 mg of naloxone hydrochloride. Insome embodiments, the therapeutically effective amount is equivalent toabout 4 mg to about 8 mg of naloxone hydrochloride. In some embodiments,the therapeutically effective amount is equivalent to about 7 mg toabout 9 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 3.4 mg ofnaloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 4 mg of naloxone hydrochloride.In some embodiments, the therapeutically effective amount is equivalentto about 5 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 6 mg of naloxonehydrochloride. In some embodiments, the therapeutically effective amountis equivalent to about 7 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about8 mg of naloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 9 mg of naloxone hydrochloride.In some embodiments, the therapeutically effective amount is equivalentto about 10 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 11 mg ofnaloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 12 mg of naloxone hydrochloride.In some embodiments, the opioid antagonist is the only pharmaceuticallyactive compound in pharmaceutical composition. In some embodiments, theopioid antagonist is naloxone hydrochloride. In some embodiments, theopioid antagonist is anhydrous naloxone hydrochloride. In someembodiments, the opioid antagonist is the only pharmaceutically activecompound in said pharmaceutical composition. In some embodiments, theopioid antagonist is naloxone hydrochloride. In some embodiments, thepharmaceutical composition comprises a solution of naloxonehydrochloride. In some embodiments, the nasally administering isaccomplished using a device described herein. In some embodiments, theopioid overdose symptom is selected from: respiratory depression,postoperative opioid respiratory depression, altered levelconsciousness, miotic pupils, cardiovascular depression, hypoxemia,acute lung injury, aspiration pneumonia, sedation, and hypotension. Insome embodiments, the opioid overdose symptom is respiratory depressioninduced by opioids. In some embodiments, the respiratory depression iscaused by the illicit use of opioids or by an accidental misuse ofopioids during medical opioid therapy. In some embodiments, therespiratory depression is induced by opioids selected from: natural andsynthetic narcotics, propoxyphene, methadone, nalbuphine, pentazocineand butorphanol. In some embodiments, the respiratory depression isinduced by an opioid agonist selected from codeine, morphine, methadone,fentanyl, oxycodone HCl, hydrocodone bitartrate, hydromorphone,oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, andtapentadol.

Also provided are devices, kits, and pharmaceutical formulations for,and methods of, treating opioid overdose or a symptom thereof,comprising nasally administering to a patient in need thereof atherapeutically effective amount of an opioid antagonist together and atleast one known pharmaceutical agent. In some embodiments, the methodcomprises nasally administering to a patient in need thereoftherapeutically effective amounts of a short-acting opioid antagonistand a long-acting opioid antagonist. In some embodiments, the methodcomprises nasally administering to a patient in need thereoftherapeutically effective amounts of naloxone and naltrexone. In someembodiments, the method comprises nasally administering to a patient inneed thereof therapeutically effective amounts of naloxone andmethylnaltrexone. In some embodiments, the method comprises nasallyadministering to a patient in need thereof therapeutically effectiveamounts of naloxone and nalmefene.

Also provided are devices, kits, and pharmaceutical formulations for,and methods of, reversing the psychotomimetic and dysphoric effects ofagonist-antagonists such as pentazocine, comprising nasallyadministering to a patient in need thereof a therapeutically effectiveamount of an opioid antagonist selected from naloxone andpharmaceutically acceptable salts thereof, wherein the therapeuticallyeffective amount is equivalent to about 2 mg to about 12 mg of naloxonehydrochloride. In some embodiments, the therapeutically effective amountis equivalent to about 4.4 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about4 mg of naloxone hydrochloride dihydrate. In some embodiments, thenasally administering is accomplished using a device described herein.

Also provided are devices, kits, and pharmaceutical formulations for,and methods of, diagnosis of suspected acute opioid overdosage,comprising nasally administering to a patient in need thereof atherapeutically effective amount of an opioid antagonist selected fromnaloxone and pharmaceutically acceptable salts thereof, wherein thetherapeutically effective amount is equivalent to about 2 mg to about 12mg of naloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 4 mg of naloxone hydrochloride.In some embodiments, the therapeutically effective amount is equivalentto about 4.4 mg of naloxone hydrochloride dihydrate. In someembodiments, the nasally administering is accomplished using a devicedescribed herein.

Also provided are devices, kits, and pharmaceutical formulations for,and methods of, treating opioid addiction, comprising nasallyadministering to a patient in need thereof a therapeutically effectiveamount of an opioid antagonist selected from naloxone andpharmaceutically acceptable salts thereof, wherein the therapeuticallyeffective amount is equivalent to about 2 mg to about 12 mg of naloxonehydrochloride. In some embodiments, the therapeutically effective amountis equivalent to about 4 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about4.4 mg of naloxone hydrochloride dihydrate. In some embodiments, thenasally administering is accomplished using a device described herein.

Also provided are devices, kits, and pharmaceutical formulations for,and methods of, treating septic shock, comprising nasally administeringto a patient in need thereof a therapeutically effective amount of anopioid antagonist selected from naloxone and pharmaceutically acceptablesalts thereof, wherein the therapeutically effective amount isequivalent to about 2 mg to about 12 mg of naloxone hydrochloride. Insome embodiments, the therapeutically effective amount is equivalent toabout 4 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 4.4 mg ofnaloxone hydrochloride dihydrate. In some embodiments, the nasallyadministering is accomplished using a device described herein.

Also provided are devices, kits, and pharmaceutical formulations for,and methods of, treating opioid overdose or a symptom thereof, reversingthe psychotomimetic and dysphoric effects of agonist-antagonists such aspentazocine, diagnosing suspected acute opioid overdosage, treatingopioid addiction, or treating septic shock, comprising nasallyadministering to a patient in need thereof a therapeutically effectiveamount of an opioid antagonist, wherein the therapeutically effectiveamount is about 2 mg to about 12 mg. In some embodiments, thetherapeutically effective amount is equivalent to about 4.4 mg ofnaloxone hydrochloride dihydrate. In some embodiments, thetherapeutically effective amount is equivalent to about 4 mg of naloxonehydrochloride. In some embodiments, the patient is an opioid overdosepatient. In some embodiments, the patient is not breathing. In someembodiments, the opioid antagonist is the only pharmaceutically activecompound in said pharmaceutical composition. In some embodiments, theopioid antagonist is selected from naltrexone, methylnaltrexone, andnalmefene, and pharmaceutically acceptable salts thereof. In someembodiments, the opioid antagonist is naltrexone hydrochloride. In someembodiments, the opioid antagonist is methylnaltrexone bromide. In someembodiments, the opioid antagonist is nalmefene hydrochloride. In someembodiments, the nasally administering is accomplished using a devicedescribed herein. In some embodiments, the opioid overdose symptom isselected from: respiratory depression, postoperative opioid respiratorydepression, altered level consciousness, miotic pupils, cardiovasculardepression, hypoxemia, acute lung injury, aspiration pneumonia,sedation, and hypotension. In some embodiments, the opioid overdosesymptom is respiratory depression induced by opioids. In someembodiments, the respiratory depression is caused by the illicit use ofopioids or by an accidental misuse of opioids during medical opioidtherapy. In some embodiments, the respiratory depression is induced byopioids selected from: natural and synthetic narcotics, propoxyphene,methadone, nalbuphine, pentazocine and butorphanol. In some embodiments,the respiratory depression is induced by an opioid agonist selected fromcodeine, morphine, methadone, fentanyl, oxycodone HCl, hydrocodonebitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium,heroin, tramadol, and tapentadol.

Various eating disorders, including binge eating, bulimia, andstimulus-induced over-eating, develop because the behaviors arereinforced by the opioidergic system so often and so well that theperson no longer can control the behavior. Thus eating disordersresemble opiate addiction and alcoholism. Accordingly, also provided aredevices, kits, and pharmaceutical formulations for, and methods of,treating an eating disorder selected from binge eating, bulimia, andstimulus-induced over-eating, comprising nasally administering to apatient in need thereof a therapeutically effective amount of an opioidantagonist, wherein the therapeutically effective amount is about 2 mgto about 12 mg. In some embodiments, the therapeutically effectiveamount is equivalent to about 4 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about4.4 mg of naloxone hydrochloride. In some embodiments, the opioidantagonist is the only pharmaceutically active compound in saidpharmaceutical composition. In some embodiments, the opioid antagonistis selected from naltrexone, methylnaltrexone, and nalmefene, andpharmaceutically acceptable salts thereof. In some embodiments, theopioid antagonist is naltrexone hydrochloride. In some embodiments, theopioid antagonist is methylnaltrexone bromide. In some embodiments, theopioid antagonist is nalmefene hydrochloride. In some embodiments, thenasally administering is accomplished using a device described herein.

Also provided are embodiments wherein any embodiment above in paragraphs[188]-[0240] above may be combined with any one or more of theseembodiments, provided the combination is not mutually exclusive.

Receptor Occupancy

Also provided are devices for use in treating opioid overdose andsymptoms thereof and methods of using the devices, which provide a highlevel of brain opioid receptor occupancy as may be determined, forexample, by positron emission tomography (PET). PET and single-photonemission computed tomography (SPECT) are noninvasive imaging techniquesthat can give insight into the relationship between target occupancy anddrug efficacy, provided a suitable radioligand is available. AlthoughSPECT has certain advantages (e.g., a long half-life of theradionuclides), the spatial and temporal resolution as well as thelabeling possibilities of this technique are limited.

PET involves the administration to a subject of a positron-emittingradionuclide tracer followed by detection of the positron emission(annihilation) events in the body. The radionuclide tracer is typicallycomposed of a targeting molecule having incorporated therein one or moretypes of positron-emitting radionuclides. Positron-emittingradionuclides include ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ⁵²Fe, ⁶²Cu, ⁶⁴Cu, ⁶⁸Ga, ⁷⁴As,⁸²Rb, ⁸⁹Zr, ¹²²I, and ¹²⁴I. Non-metal radionuclides may be covalentlylinked to the targeting molecule by reactions well known from the stateof art. When the radionuclide is a metallic positron-emitter, it isunderstood that labeling may require the use of a chelating agent. Suchchelating agents are well known from the state of the art.

The positron-emitter labeled compound is administered directly, e.g.,IV, or indirectly, e.g., IN, into the subject's vascular system, fromwhere it passes through the blood-brain barrier. Once the tracer has hadsufficient time to associate with the target of interest, the individualis placed within in a scanning device comprising ring of scintillationdetectors. An emitted positron travels through the individual's tissuefor a short (isotope-dependent) distance, until it interacts with anelectron. The interaction annihilates both the electron and thepositron, producing a pair of photons moving in approximately oppositedirections. These are detected when they reach a scintillator in thescanning device. Photons that do not arrive in pairs are ignored. Animage is then generated of the part of the individual's brain to whichthe compound has distributed.

PET studies are useful for comparing nasal delivery of naloxone usingthe devices and at the doses described herein, to typical nasal doses ofnaloxone (such as 1-2 mg), to delivery of naloxone using other nasaldevices (such as the MAD™) and by other routes of administration such IMor IV naloxone or oral naltrexone or nalmefene. Further comparisons maybe made between nasal administration in the upright versus the lying orsupine positions. Useful measures that may be determined in such studiesare the time to onset of action, brain half-life, and the percentreceptor binding or occupancy of a patient's opioid receptors, forexample, the μ-opioid receptors in the respiratory center in the medullaoblongata.

[¹¹C]Carfentanil (CFN) is a μ-opioid agonist used for in vivo PETstudies of μ-opioid receptors. One such study involved healthy malevolunteers assigned at enrolment to receive either naltrexone or a novelμ-opioid receptor inverse agonist (GSK1521498) (Rabiner et al.,Pharmacological differentiation of opioid receptor antagonists bymolecular and functional imaging of target occupancy and foodreward-related brain activation in humans. Molecular Psychiatry (2011)16, 826-835). Each participant underwent up to three [¹¹C]-carfentanilPET scans and two fMRI examinations: one [¹¹C]-carfentanil PET scan andone fMRI scan at baseline (before dosing) and up to two PET scans andone fMRI scan following oral administration of a single dose ofGSK1521498 or naltrexone. The administered doses of GSK1521498 ornaltrexone were chosen adaptively to optimize the estimation of thedose-occupancy relationship for each drug on the basis of data acquiredfrom the preceding examinations in the study. The administered doserange was 0.4-100 mg for GSK1521498, and 2-50 mg for naltrexone. Themaximum doses administered were equal to the maximum tolerated dose ofGSK1521498 determined in the first-in-human study and the standardclinical dose of naltrexone used for alcohol dependence. The times anddoses of the two post-dose [¹¹C]-carfentanil PET scans were chosenadaptively for each subject to optimize estimation of the relationshipbetween plasma concentration and receptor occupancy. Post-dose[¹¹C]-carfentanil PET scans were acquired at 3-36 h after theadministration of GSK1521498 and at 3-88 h after the administration ofnaltrexone. Post-dose fMRI scans were acquired within 60 min of thefirst post-dose PET scan. Venous blood samples were collected at regularintervals throughout the scanning sessions. High-performance liquidchromatography/mass spectrometry/mass spectrometry was used to estimatethe plasma concentrations of GSK1521498, naltrexone, and the majormetabolite of naltrexone, 6-β-naltrexol. Drug plasma concentration atthe start of each PET scan was used to model the relationship betweendrug concentrations and μ-opioid receptor occupancies. Carfentanil(methyl1-(2-phenylethyl)-4-(phenyl(propanoyl)amino)-4-piperidinecarboxylate 3S,5S; Advanced Biochemical Compounds, Radeberg, Germany), a potentselective μ-opioid receptor agonist, was labelled with carbon-11 using amodification of a previously described method implemented using asemiautomated Modular Lab Multifunctional Synthetic Module (Eckert &Ziegler, Berlin, Germany). The final product was reformulated in sterile0.9% saline containing ˜10% ethanol (v/v) and satisfied quality controlcriteria for specific activity and purity before being injectedintravenously as a slow bolus over ˜30 s. PET scanning was conducted inthree-dimensional mode using a Siemens Biograph 6 Hi-Rez PET-CT for thenaltrexone group and a Siemens Biograph 6 TruePoint PET-CT for theGSK1521498 group (Siemens Healthcare, Erlangen, Germany). A low-dose CTscan was acquired for attenuation correction before the administrationof the radiotracer. Dynamic PET data were acquired for 90 min after[¹¹C]-carfentanil injection, binned into 26 frames (durations: 8×15 s,3×60 s, 5×2 min, 5×5 min and 5×10 min), reconstructed using Fourierre-binning and a two-dimensional-filtered back projection algorithm andthen smoothed with a two-dimensional Gaussian filter (5 mm at full widthhalf maximum). Dynamic PET images were registered to each participant'sT1-weighted anatomical MRI volume and corrected for head motion usingSPM5 software (Wellcome Trust Centre for Neuroimaging). Pre-selectedregions of interests were defined bilaterally on the T1-weightedanatomical volume using an in-house atlas and applied to the dynamic PETdata to generate regional time-activity curves. The[¹¹C]-carfentanil-specific binding was quantified as binding potentialrelative to the non-displaceable compartment (BPND)

${BP}_{ND} = \frac{f_{ND}B_{avail}}{K_{D}}$

where f_(ND) is the free fraction of the radioligand in the brain, K_(D)is the affinity of [¹¹C]-carfentanil, and B_(avail) is the density ofthe available μ-opioid receptors. Regional [¹¹C]-carfentanil BPND wasestimated using a reference tissue model with the occipital cortex asthe reference region. Drug related occupancy of the μ-opioid receptorwas quantified as a reduction of [¹¹C]-carfentanil.

${Occupancy}_{Drug} = \frac{{BP}_{ND}^{Baseline} - {BP}_{ND}^{Drug}}{{BP}_{ND}^{Baseline}}$

The affinity constant for each drug at the μ-opioid receptor (effectiveconcentration 50 (EC₅₀)) was estimated by fitting the plasmaconcentration measured at the start of the PET scan, C^(P) _(Drug), tothe estimated occupancy:

${Occupancy}_{Drug} = \frac{C_{Drug}^{P}}{C_{Drug}^{P} + {EC}_{50}}$

The use of a sensitive non-tomographic positron detecting system tomeasure the dose-response curve of naloxone in human brain has also beenreported. [¹¹C]Diprenorphine was administered to normal volunteers intracer amounts and, 30 min later, various bolus doses of naloxone weregiven (1.5-160 μg/kg) intravenously and change in [¹¹C]diprenorphinebinding monitored over the next 30 min. Approximately 13 μg/kg ofnaloxone (approximately 1 mg in an 80 kg man) was required to produce anestimated 50% receptor occupation, consistent with the clinical dose ofnaloxone used to reverse opiate overdose (0.4 mg-1.2 mg). Melichar etal., Naloxone displacement at opioid receptor sites measured in vivo inthe human brain. Eur J Pharmacol. 2003 Jan. 17; 459(2-3):217-9).

In some embodiments of the devices, kits, pharmaceutical formulations,and methods disclosed above, delivery of the therapeutically effectiveamount to the patient, provides occupancy at T_(max) of the opioidantagonist at the opioid receptors in the respiratory control center ofthe patient of greater than about 90%. In some embodiments, delivery ofthe therapeutically effective amount to the patient, provides occupancyat T_(max) of the opioid antagonist at the opioid receptors in therespiratory control center of the patient of greater than about 95%. Insome embodiments, delivery of the therapeutically effective amount tothe patient, provides occupancy at T_(max) of the opioid antagonist atthe opioid receptors in the respiratory control center of the patient ofgreater than about 99%. In some embodiments, delivery of thetherapeutically effective amount to the patient, provides occupancy atT_(max) of the opioid antagonist at the opioid receptors in therespiratory control center of the patient of about 100%.

Also provided are embodiments wherein any embodiment described above,particularly those in paragraphs [0248] and [087]-[0153], [0159]-[0185],and [0188]-[0228], may be combined with any one or more of theseembodiments, provided the combination is not mutually exclusive.

EXAMPLES Example 1 Pharmacokinetics and Safety of Intranasal Naloxone inHumans (Study 1)

A clinical trial was performed for which the primary objectives were todetermine the pharmacokinetics (PK) of 2 intranasal (IN) doses (2 mg and4 mg) of naloxone compared to a 0.4 mg dose of naloxone administratedintramuscularly (IM) and to identify an appropriate IN dose that couldachieve systemic exposure comparable to an approved parenteral dose. Thesecondary objectives were to determine the safety of IN naloxone,specifically with respect to nasal irritation (erythema, edema, anderosion).

Methodology: This was an inpatient open-label, randomized, 3-period,3-treatment, 6-sequence, crossover study involving 14 healthyvolunteers. Subjects were assigned to one of the 6 sequences with 2subjects in each sequence (2 sequences had 3 subjects). Each subjectreceived 3 naloxone doses, a single 2 mg IN dose (one spray of 0.1 mL of10 mg/mL solution in each nostril), a single 4 mg IN dose (2 sprays of0.1 mL per spray of 10 mg/mL solution in each nostril) and a single 0.4mg IM dose, in the 3 dosing periods (Table 1). Subjects stayed in theinpatient facility for 11 days to complete the entire study and weredischarged on the next day after the last dose. Subjects returned for afinal follow-up visit 3-5 days after discharge. After obtaining informedconsent, subjects were screened for eligibility to participate in thestudy including medical history, physical examination, clinicalchemistry, coagulation markers, hematology, infectious disease serology,urinalysis, urine drug and alcohol toxicology screen, vital signs andelectrocardiogram (ECG). On the day after clinic admission, subjectswere administered study drug in randomized order with a 4-day washoutperiod between doses until all three doses were administered. Blood wascollected for naloxone PK prior to dosing and approximately 2.5, 5, 10,15, 20, 30, 45, 60, 120, 180, 240, 300, 360, 480 and 720 min after thestart of study drug administration. On days of study drugadministration, a 12-lead ECG was performed approximately 60 min priorto dosing and at approximately 60 and 480 min post-dose. Vital signswere measured pre-dose and approximately 30, 60, 120, and 480 minpost-dose. On dosing days, the order of assessments was ECG, vitalsigns, then PK blood collection when scheduled at the same nominaltimes. ECG and vital signs were collected within the 10-min periodbefore the nominal time of blood collections. At screening, admission,discharge, and follow-up, ECG and vital signs were checked once per day.Vital signs were also checked once on the day after naloxoneadministration. Clinical laboratory measurements were repeated after thelast PK blood draw prior to clinic discharge. AEs were assessed byspontaneous reports by subjects, examination of the nasal mucosa,physical examination, vital signs, ECG, and clinical laboratoryparameters.

Main Criteria for Inclusion/Exclusion: Healthy volunteer adults with abody mass index (BMI) of 18-30 kg/m².

Investigational Product, Dose and Mode of Administration: Naloxone givenIN was at a dose of 2 mg (1 squirt in each nostril delivered 0.1 mL of10 mg/mL naloxone) and 4 mg (2 squirts in each nostril delivered 0.2mL/nostril at 10 mg/mL naloxone, using two devices). IN naloxone wasadministered using a Pfeiffer (Aptar) BiDose liquid device with thesubject in a fully supine position.

Duration of Treatment: Each IN and IM dose was administered once in eachsubject in random sequence.

Reference Therapy, Dose and Mode of Administration: Naloxone was givenIM at a dose of 0.4 mg in 1.0 mL with a 23-g needle as a singleinjection in the gluteus maximus muscle.

PK Evaluation: Blood was collected in sodium heparin containing tubesfor naloxone PK prior to dosing and 2.5, 5, 10, 15, 20, 30, 45, 60, 120,180, 240, 300, 360, 480, and 720 min after the start of study drugadministration. Non-compartmental PK parameters including C_(max),T_(max) AUC to infinity (AUC_(0-∞)), AUC to last measurableconcentration (AUC_(0-t)), t_(1/2), λ_(z), and apparent clearance (CL/F)were determined. Values of t_(1/2) were determined from the log-lineardecline in plasma concentrations from 2 to 6 or 8 h.

Safety Evaluation: Heart rate, blood pressure, and respiration rate wasrecorded before naloxone dosing and at approximately 30, 60, 120, and480 min after dosing. These vital signs and temperature were alsomeasured at screening, clinic intake, one day after each dosing sessionand at follow-up. A 12-lead ECG was obtained prior to and approximately60 and 480 min after each naloxone dose, as well as during screening,clinic intake, and follow-up. ECG and vital signs were taken within the10-min period before the nominal time for blood collections. AEs wererecorded from the start of study-drug administration until clinicdischarge. AEs were recorded relative to each dosing session to attemptto establish a relationship between the AE and type of naloxone doseadministered. An examination of the nasal passage was conducted at Day-1to establish eligibility and at pre-dose, 5 min, 30 min, 60 min, 4 h,and 24 h post naloxone administration to evaluate evidence of irritationto the nasal mucosa. Clinical laboratory measurements were done prior tothe first drug administration and on the day of clinic release.

Statistical Analysis of PK Parameters: C_(max), T_(max) and AUC for 2and 4 mg IN naloxone were compared with those for 0.4 mg IM naloxone.Within an ANOVA framework, comparisons of natural log (LN) transformedPK parameters (C_(max) and AUC) for IN versus IM naloxone treatmentswere performed. The 90% confidence interval (CI) for the ratio (IN/IM)of the least squares means of AUC and C_(max) parameters wasconstructed. These 90% CI were obtained by exponentiation of the 90%confidence intervals for the difference between the least squares meansbased upon a LN scale. In addition, dose adjusted values for AUCs andC_(max) based upon a 0.4 mg dose were calculated (Tables 4-7). Therelative extent of absorption (relative bioavailability, F_(rel)) ofintranasal (IN versus IM) was estimated from the dose-corrected AUCs.

Statistical Analysis of Adverse Events: AEs were coded using the mostrecent version of the Medical Dictionary for Regulatory Activities(MedDRA). Preferred terms and are grouped by system, organ, class (SOC)designation. AEs are presented as a listing including the start date,stop date, severity, relationship, outcome, and duration.

Pharmacokinetics Results: The mean dose delivered for the 2 mg INnaloxone dose was 1.71 mg (range 1.50 mg to 1.80 mg) and for the 4 mg INnaloxone dose it was 3.40 mg (range 2.93 mg to 3.65 mg). This was 84-85%of the target dose. The overall % coefficient of variation (% CV) forthe delivered dose from all 42 devices was 6.9% (Table 9). Preparationtime of the IN doses took less than one third of the time to prepare theIM injection (70 seconds for the IM injection and 20 seconds for the INadministration) (Table 8). The time to prepare the IM injection did notinclude loading the syringe. Since the one purpose of the study was todetermine if peak naloxone plasma concentrations (C_(max)) and AUCsfollowing IN 2 mg and IN 4 mg administrations were equivalent to, orgreater than IM 0.4 mg dosing, AUCs and C_(max) values were comparedwithout considering the dose difference among treatments. The C_(max),AUC_(0-t), and AUC_(0-∞) for both the 2 mg IN and 4 mg IN doses werestatistically significantly greater than those for the 0.4 mg IM dose(p<0.001). The geometric least square means for C_(max) were 2.18 ng/mL,3.96 ng/mL, and 0.754 ng/mL for IN 2 mg, IN 4 mg and IM 0.4 mg,respectively. The geometric least square means for AUC_(0-∞) were 3.32ng·h/mL, 5.47 ng·h/mL and 1.39 ng·h/mL for IN 2 mg, IN 4 mg and IM 0.4mg respectively. The geometric least squares mean ratios for IN 2 mg/IM0.4 mg were 290% for C_(max) and 239% for AUC_(0-∞). The ratios for IN 4mg/IM 0.4 mg were 525% for C_(max) and 394% for AUC_(0-∞). There were nostatistically significant differences between the routes and doses withrespect to T_(max), suggesting peak effects would occur at similar timesfor all treatments. However, the mean T_(max) values did trend lower forthe IN route versus IM, and for 4 mg IN versus 2 mg IN. (See Table 2).In comparing the extent of systemic absorption of IN to IM dosing, theF_(rel) estimates were 55.7% and 46.3% for IN 2 mg and 4 mg,respectively. See Table 3.

Safety Results: No erythema, edema, erosion, or other sign was observedin the nasal cavity prior to or after any IN administration of naloxoneat 2 and 4 mg to both nostrils. One subject experienced mild transient(over 3 min) pharyngeal pain coincident with the application of the 2 mgIN dose. This pain resolved spontaneously. Vital signs, ECG, andclinical laboratory parameters did not reveal any clinically noteworthychanges after naloxone administration. There was no evidence of QTcFprolongation.

TABLE 1 Order of Naloxone Doses and Route of Administration for eachSubject Dosing Dosing Dosing Subject Session #1 Session #2 Session #3 #ID Sequence # Day 1 Day 5 Day 9 1 102 5 4 mg IN 2 mg IN 0.4 mg IM 2 1076 0.4 mg IM 4 mg IN 2 mg IN 3 112 1 2 mg IN 4 mg IN 0.4 mg IM 4 117 30.4 mg IM 2 mg IN 4 mg IN 5 120 1 2 mg IN 4 mg IN 0.4 mg IM 6 123 2 4 mgIN 0.4 mg IM 2 mg IN 7 127 3 0.4 mg IM 2 mg IN 4 mg IN 8 128 5 4 mg IN 2mg IN 0.4 mg IM 9 133 2 4 mg IN 0.4 mg IM 2 mg IN 10 113 4 2 mg IN 0.4mg IM 4 mg IN 11 114 1 2 mg IN 4 mg IN 0.4 mg IM 12 119 6 0.4 mg IM 4 mgIN 2 mg IN 13 125 4 2 mg IN 0.4 mg IM 4 mg IN 14 135 5 4 mg IN 2 mg IN0.4 mg IM

TABLE 2 Summary of Naloxone Pharmacokinetic Parameters FollowingNaloxone as 0.4 mg Intramuscular (IM), 2 mg Intranasal (IN), and 4 mg INAdministrations 0.4 mg IM 2 mg IN 4 mg IN Parameter Mean % CV Mean % CVMean % CV Dose (mg) 0.400 — 1.714 5.7 3.403 5.7 C_(max) (ng/mL) 0.76527.6 2.32 41.2 4.55 63.7 T_(max) (min) 20.34 36.1 19.98 31.0 18.42 33.6AUC_(0-t) 1.38 19.9 3.41 29.5 5.63 27.6 ng · h/mL AUC_(0-∞) 1.42 19.23.44 29.3 5.68 27.6 (ng · h/mL) λ_(z) (1/h) 0.593 16.6 0.588 0.572 8.010.2 t_(1/2) (h) 1.21 20.1 1.19 8.3 1.22 10.2

TABLE 3 Summary of Naloxone Pharmacokinetic Parameters FollowingNaloxone as 0.4 mg Intramuscular (IM), 2 mg Intranasal (IN), and 4 mg INAdministrations with Dose Normalized to 0.4 mg 0.4 mg IM 2 mg IN 4 mg INParameter Mean % CV Mean % CV Mean % CV AUC_(0-t/D) ng · h/mL 1.38 19.90.796 28.7 0.667 29.4 AUC_(0-∞/D) ng · h/mL 1.42 19.2 28.5 0.674 0.80429.3 F_(rel) 0.571 24.5 0.475 25.3

TABLE 4 Statistical Comparison of Geometric Least Squares Mean (GLSM) ofPharmacokinetic Parameters for IN Naloxone at a Dose of 2 mg to IMNaloxone at a Dose of 0.4 mg with No Dose Adjustment GLSM GLSM GLSM 0.4mg Ratio 90% CI of Parameter 2 mg IN IM IM/IN % Ratio p-value C_(max)(ng/mL) 2.18 0.754 290 237-353 <0.001 T_(max) (h) 1.000 0.333 0.308 — —— AUC_(0-t) (ng · h/mL) 3.28 1.35 243 219-270 <0.001 AUC_(0-∞) (ng ·h/mL) 3.32 1.39 239 215-264 <0.001 t_(1/2) (h) 1.18 1.19 102 94.0-111 0.6507

TABLE 5 Statistical Comparison of Geometric Least Squares Mean (GLSM) ofPharmacokinetic Parameters for IN Naloxone at a Dose of 4 mg to IMNaloxone at a Dose of 0.4 mg with No Dose Adjustment GLSM GLSM GLSM 0.4mg Ratio 90% CI of Parameter 4 mg IN IM IM/IN % Ratio p-value C_(max)(ng/mL) 3.96 0.754 525 431-640 <0.001 T_(max) (h) 1.000 0.292 0.3080.418 AUC_(0-t) (ng · h/mL) 5.41 1.35 401 361-445 <0.001 AUC_(0-∞) (ng ·h/mL) 5.47 1.39 394 355-436 <0.001 t_(1/2) (h) 1.22 1.19 102 94.0-111 0.651

TABLE 6 Statistical Comparison of Geometric Least Squares Mean (GLSM) ofPharmacokinetic Parameters for IN Naloxone at a Dose of 2 mg to IMNaloxone at a Dose of 0.4 mg with Dose Adjustment to 0.4 mg GLSM GLSMGLSM 0.4 mg Ratio 90% CI of Parameter 2 mg IN IM IM/IN % Ratio p-valueC_(max/D) (ng/mL) 0.510 0.755 67.6 55.3-82.7 0.0028 T_(max) (h) 0.3330.308 — — 1.000 AUC_(0-t/D) (ng · h/ 0.767 1.35 56.8 50.8-63.4 <0.001mL) AUC_(0-∞/D) (ng · h/ 0.775 1.39 55.7 50.0-62.1 <0.001 mL) t_(1/2)(h) 1.18 1.19 99.3 91.3-108  0.8963

TABLE 7 Statistical Comparison of Comparison of Geometric Least SquaresMean (GLSM) Pharmacokinetic Parameters for IN Naloxone at a Dose of 4 mgto IM Naloxone at a Dose of 0.4 mg with Dose Adjustment to 0.4 mg GLSMGLSM GLSM 0.4 mg Ratio 90% CI of Parameter 4 mg IN IM IM/IN % Ratiop-value C_(max/D) (ng/mL) 0.466 0.755 61.7 50.5-75.5 <0.001 T_(max) (h)0.292 0.308 — — 0.418 AUC_(0-t/D) (ng · h/ 0.637 1.35 47.2 42.2-52.7<0.001 mL) AUC_(0-∞/D) (ng · h/ 0.644 1.39 46.3 41.5-51.6 <0.001 mL)t_(1/2) (h) 1.22 1.19 102   94.0-111  0.651

TABLE 8 Time to Prepare the IM and IN Doses for Administration Time(seconds) IM Dose 2 mg IN Dose 4 mg IN Dose N 14 14 14 Mean 70 19 23 SD10 4 3 Median 73 19 23 Minimum 50 15 18 Maximum 82 30 28

TABLE 9 Estimated IN Dose Delivered (mg) All 2 mg Dose 4 mg Dose DevicesTotal First Device Second Device Total Total N 14 14 14 14 42 Mean 1.6971.682 1.687 3.369 1.689 SD 0.097 0.156 0.092 0.193 0.116 % CV 5.7 9.35.4 5.7 6.9 Median 1.708 1.711 1.704 3.410 1.710 Minimum 1.481 1.3151.506 2.898 1.315 Maximum 1.838 1.824 1.803 3.616 1.838

Example 2 Pharmacokinetics and Safety of Intranasal Naloxone in Humans(Study 2)

A second study was undertaken to determine the pharmacokinetics (PK) andbioavailability of intranasally-delivered naloxone compared tointramuscularly-injected naloxone.

Objectives.

Specifically, the study had several objectives. The first was todetermine the pharmacokinetics (i.e., the C_(max), T_(max), AUC_(0-inf)and AUC_(0-t)) of 4 intranasal doses—2 mg, 4 mg (2 nostrils), 4 mg (1nostril), and 8 mg (2 nostrils)—of naloxone compared to a 0.4 mg dose ofnaloxone administrated IM and to identify an appropriate IN dose thatcould achieve systemic exposure comparable to an approved parenteraldose. The second was to determine the pharmacokinetics of two differentconcentrations (20 mg/mL and 40 mg/mL) of IN naloxone. The third was todetermine the safety of IN naloxone, including adverse events, vitalsigns, and clinical laboratory changes, specifically with respect tonasal irritation (erythema, edema, and erosion).

Design.

The study was an inpatient open-label, randomized. 5-period,5-treatment, 5-sequence, crossover study involving approximately 30healthy volunteers, randomized to have at least 24 subjects who completeall study drug administrations and blood collections for PK assessments.Subjects were assigned to one of the 5 sequences and there were 6subjects in each. Each subject received 5 naloxone treatments during the5 dosing periods: a single 2 mg IN dose (one 0.1 mL spray of a 20 mg/mLsolution in one nostril), a 4 mg IN dose (one 0.1 mL spray of a 20 mg/mLsolution in each nostril), a single 4 mg IN dose (one 0.1 mL spray of a40 mg/mL solution in one nostril), a single 8 mg IN dose (one 0.1 mLspray of a 40 mg/mL solution in each nostril), and a single 0.4 mg IMdose. Subjects stayed in an inpatient facility for 18 days to completethe entire study and were discharged on the next day after the lastdose. Subjects returned for a final follow-up visit 3 to 5 days afterdischarge.

After obtaining informed consent, subjects were screened for eligibilityto participate in the study including medical history, physicalexamination, clinical chemistry, coagulation markers, hematology,infectious disease serology, urinalysis, urine drug and alcoholtoxicology screen, vital signs and ECG.

Inclusion criteria were: men or women 18 to 55 years of age, inclusive;written informed consent; BMI ranging from 18 to 30 kg/m2, inclusive;adequate venous access; no clinically significant concurrent medicalconditions; agreement to use a reliable double-barrier method of birthcontrol from the start of screening until one week after completing thestudy (oral contraceptives are prohibited); and agreement not to ingestalcohol, drinks containing xanthine>500 mg/day, or grapefruit/grapefruitjuice, or participate in strenuous exercise 72 hours prior to admissionthrough the last blood draw of the study.

Exclusion criteria were: any IN conditions including abnormal nasalanatomy, nasal symptoms (i.e., blocked and/or runny nose, nasal polyps,etc.), or having a product sprayed into the nasal cavity prior to drugadministration; taking prescribed or over-the-counter medications,dietary supplements, herbal products, vitamins, or recent use of opioidanalgesics for pain relief (within 14 days of last use of any of theseproducts); positive urine drug test for alcohol, opioids, cocaine,amphetamine, methamphetamine, benzodiazepines, tetrahydrocannabinol(THC), barbiturates, or methadone at screening or admission; previous orcurrent opioid, alcohol, or other drug dependence (excluding nicotineand caffeine), based on medical history; subject consumes greater than20 cigarettes per day on average, in the month prior to screening, orwould be unable to abstain from smoking (or use of anynicotine-containing substance) for at least one hour prior to and 2hours after naloxone dosing; on standard 12-lead ECG, a QTcFinterval>440 msec for males and >450 msec for females; significant acuteor chronic medical disease in the judgment of the investigator; a likelyneed for concomitant treatment medication during the study; donated orreceived blood or underwent plasma or platelet apheresis within the 60days prior to the day before study commencement; female who is pregnant,breast feeding, or plans to become pregnant during the study period orwithin one week after naloxone administration; positive test forhepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCVAb)or human immunodeficiency virus antibody (HIVAb) at screening; andcurrent or recent (within 7 days prior to screening) upper respiratorytract infection.

Naloxone for IM injection manufactured by Hospira was obtained from alicensed distributor at a concentration of 0.4 mg/mL and was given IM ata dose of 0.4 mg in 1.0 mL with a 23-g needle as a single injection inthe gluteus maximus muscle. Naloxone for IN administration was obtainedfrom Lightlake Therapeutics, Inc., London, United Kingdom at twoconcentrations of 20 mg/mL and 40 mg/mL, and was given as doses of 2 mg(one 0.1 mL spray of the 20 mg/mL formulation in one nostril), 4 mg (two0.1 mL sprays of the 20 mg/mL formulation in two nostrils), 4 mg (one0.1 mL spray of the 40 mg/mL formulation in one nostril) and 8 mg (two0.1 mL sprays of the 40 mg/mL formulation in two nostril). IN naloxonewas administered using an Aptar single dose device with the subject in afully supine position. Subjects were to be instructed to not breathethrough the nose when the IN dose of naloxone was administered.

On the day after clinic admission, subjects were administered study drugin randomized order with a 4-day washout period between doses until all5 treatments were administered. Blood was collected for naloxone PKprior to dosing and approximately 2.5, 5, 10, 15, 20, 30, 45, 60, 120,180, 240, 300, 360, 480 and 720 minutes after the start of study drugadministration, into sodium heparin containing tubes. On days of studydrug administration, a 12-lead ECG was performed approximately 60minutes prior to dosing and at approximately 60 and 480 minutespost-dose. Vital signs were measured pre-dose and approximately 30, 60,120, and 480 minutes post-dose. On dosing days, the order of assessmentswere ECG, vital signs, then PK blood collection when scheduled at thesame nominal times. The target time of the PK blood collection wasconsidered the most important, and if the collection was more than ±1minute from the scheduled time for the first 60 minutes of collectionsor more than ±5 minutes for the scheduled time points thereafter, thiswas considered a protocol deviation. ECG and vital signs were collectedwithin the 10 minute period before the nominal time of bloodcollections. At screening, admission, discharge, and follow-up, ECG andvital signs were checked once per day. Vital signs were also checkedonce on the day after naloxone administration. Clinical laboratorymeasurements were repeated after the last PK blood draw prior to clinicdischarge. Adverse events were assessed by spontaneous reports bysubjects, by examination of the nasal mucosa, by measuring vital signs,ECG, and clinical laboratory parameters.

Results are shown below in Table 9, which sets forth the mean from 28healthy subjects (and SD, in parentheses) plasma concentrations ofnaloxone following single intranasal administrations and anintramuscular injection, and in FIGS. 3 and 4.

TABLE 9 One Spray - Two Sprays - One Spray - Two Sprays - Time 2 mg 4 mg4 mg 8 mg (min) 20 mg/mL IN 20 mg/mL IN 40 mg/mL IN 40 mg/mL IN 0.4 mgIM 0 0.000 (0.000) 0.000 (0.000) 0.000 (0.000) 0.000 (0.000) 0.000(0.000) 2.5 0.175 (0.219) 0.725 (0.856) 0.280 (0.423) 0.880 (1.21) 0.081(0.135) 5 0.882 (0.758) 2.68 (2.65) 1.50 (1.76) 3.73 (4.02) 0.305(0.336) 10 2.11 (1.33) 4.60 (2.59) 3.24 (2.21) 7.61 (5.28) 0.566 (0.318)15 2.74 (1.07) 5.56 (2.20) 4.00 (2.24) 8.02 (3.60) 0.678 (0.312) 20 2.89(1.14) 5.82 (1.74) 4.57 (2.30) 8.06 (2.56) 0.747 (0.271) 30 2.52 (0.810)5.15 (1.70) 4.50 (1.93) 7.89 (1.95) 0.750 (0.190) 45 2.17 (0.636) 4.33(1.16) 4.03 (1.57) 6.84 (1.69) 0.689 (0.171) 60 1.88 (0.574) 3.69(0.887) 3.35 (1.17) 5.86 (1.40) 0.610 (0.143) 120 0.823 (0.335) 1.63(0.626) 1.57 (0.773) 2.86 (0.927) 0.354 (0.107) 180 0.390 (0.146) 0.800(0.253) 0.771 (0.412) 1.42 (0.487) 0.227 (0.082) 240 0.215 (0.100) 0.452(0.225) 0.412 (0.215) 0.791 (0.275) 0.135 (0.058) 300 0.117 (0.051)0.243 (0.123) 0.246 (0.143) 0.431 (0.166) 0.074 (0.047) 360 0.068(0.030) 0.139 (0.067) 0.146 (0.081) 0.257 (0.104) 0.040 (0.022) 4800.031 (0.014) 0.068 (0.033) 0.065 (0.038) 0.122 (0.052) 0.013 (0.015)720 0.009 (0.009) 0.027 (0.013) 0.026 (0.019) 0.053 (0.025) 0.001(0.003)

For pharmacokinetic analysis, plasma was separated from whole blood andstored frozen at ≦−20° C. until assayed. Naloxone plasma concentrationswas determined by liquid chromatography with tandem mass spectrometry.Conjugated naloxone plasma concentrations may also be determined.Non-compartmental PK parameters including C_(max), T_(max), AUC_(0-inf),AUC_(0-t), t_(1/2), λ_(z), and apparent clearance (CL/F) weredetermined. Pharmacokinetic parameters (C_(max), T_(max), and AUCs) forIN naloxone were compared with those for IM naloxone. T_(max) was fromthe time of administration (spraying into the nasal cavity or IMinjection). Dose adjusted values for AUCs and C_(max) were thencalculated, and the relative extent of intranasal absorption (IN versusIM) estimated from the dose-corrected AUCs. Within an ANOVA framework,comparisons of ln-transformed PK parameters (C_(max) and AUC) forintranasal versus IM naloxone treatments were performed. The 90%confidence interval for the ratio (IN/IM) of the geometric least squaresmeans of AUC and C_(max) parameters were constructed for comparison ofeach treatment with IM naloxone. These 90% CIs were obtained byexponentiation of the 90% confidence intervals for the differencebetween the least squares means based upon an ln scale.

Results are shown below in Table 10, which sets forth the mean plasma PKparameters from 28 healthy subjects (and % CV, in parentheses) ofnaloxone following single intranasal administrations and anintramuscular injection, and in Table 11, which sets forth the same PKparameters split between the 12 female and 16 male healthy subjects.

TABLE 10 One Spray - Two Sprays - One Spray - Two Sprays - 2 mg 4 mg 4mg 8 mg Parameter 20 mg/mL 20 mg/mL 40 mg/mL 40 mg/mL (units) IN IN ININ 0.4 mg IM C_(max) (ng/ml) 3.11 (36.3) 6.63 (34.2) 5.34 (44.1) 10.3(38.8) 0.906 (31.5)  C_(max) per mg 1.56 (36.3) 1.66 (34.2) 1.34 (44.1)1.29 (38.8) 2.26 (31.5) (ng/mL) T_(max) (h)^(a) 0.33 (0.25, 0.33 (0.08,0.50 (0.17, 0.33 (0.17, 0.42 (0.08, (median, range) 1.00) 0.50) 1.00)1.00) 2.00) AUC_(t) 4.81 (30.3) 9.82 (27.3) 8.78 (37.4) 15.9 (23.6) 1.79(23.5) (ng · mL/h) AUC_(inf) 4.86 (30.1) 9.91 (27.1) 8.87 (37.2) 16.1(23.3) 1.83 (23.0) (ng · mL/h) AUC_(inf) per mg 2.43 (30.1) 2.48 (27.1)2.22 (37.2) 2.01 (23.3) 4.57 (23.0) (ng · mL/h) Lambda z 0.3685 0.29730.3182 0.3217 0.5534 (hr⁻¹)^(b) Half-life (h)^(b) 1.70 2.09 2.00 1.911.19 AUC % 1.09 (41.9) 1.01 (53.9) 1.06 (52.5) 1.04 (78.1) 2.32 (54.1)Extrapolate CL/F (L/h)  441 (24.5)  426 (22.3)  502 (31.2)  521 (21.7) 230 (22.4) Relative BA 53.8 (22.2) 55.3 (22.2) 49.2 (30.6) 45.3 (25.1)100 (%) vs. IM

TABLE 11 One 20 Two 20 One 40 Two 40 Parameter mg/mL IN mg/mL IN mg/mLIN mg/mL IN 0.4 mg IM (units) Female Male Female Male Female Male FemaleMale Female Male C_(max) 2.79 3.35 6.62 6.64 5.12 5.51 9.52 10.9 1.060.792 (ng/ml) C_(max) per mg 1.39 1.68 1.66 1.66 1.28 1.38 1.19 1.362.64 1.98 (ng/mL) T_(max) (h)^(a) 0.33 0.33 0.33 0.25 0.50 0.50 0.290.42 0.33 0.50 AUC_(t) 4.73 4.87 9.81 9.82 7.98 9.38 14.8 16.8 1.83 1.75(ng · mL/h) AUC_(inf) 4.78 4.93 9.91 9.92 8.06 9.48 15.0 16.9 1.88 1.79(ng · mL/h) AUC_(inf) per 2.39 2.46 2.48 2.48 2.01 2.37 1.87 2.12 4.694.47 mg (ng · mL/h) Lambda z 0.3978 0.3492 0.2796 0.3122 0.2946 0.33860.2994 0.3407 0.6140 0.5152 (hr⁻¹)^(b) Half-life 1.58 1.80 2.18 2.032.12 1.93 1.90 1.91 1.08 1.28 (h)^(b) AUC % 0.971 1.19 0.986 1.02 0.9701.12 1.12 0.992 2.31 2.32 Extrapolate CL/F (L/h) 449 434 419 431 555 462558 494 222 236

In the tables above, the notation a indicates median (range) isdisclosed, and the notation b indicates harmonic mean is disclosed.

Additional exploratory analyses could include:

-   -   1) 90% CI for dose corrected AUC and C_(max) between the 20        mg/mL formulation treatment and 40 mg/mL formulation for both a        single administration and two dose administration (once in each        nostril) for dose linearity purpose;    -   2) 90% CI adjusted for dose for geometric ratios of one 0.1 mL        spray (in one nostril) vs. a two 0.1 mL sprays (one spray in        each nostril) from an 20 mg/mL formulation; and    -   3) 90% CI adjusted for dose for geometric ratios of one 0.1 mL        spray (in one nostril) vs. a two 0.1 mL sprays (one spray in        each nostril) from an 40 mg/mL formulation;

AEs were coded using the most recent version of the Medical Dictionaryfor Regulatory Activities (MedDRA) preferred terms and grouped bysystem, organ, class (SOC) designation. Separate summaries will beprovided for the 5 study periods: after the administration of each doseof study drug up until the time of the next dose of study drug or clinicdischarge. Listings of each individual AE including start date, stopdate, severity, relationship, outcome, and duration were provided.Results are given below in Tables 12 and 13. Table 12 shows the eventsrelated to nasal irritation—erythema, edema, other, and total—observedin the nasally-treated group. Nasal irritation did not appear to bepositively related to the dose of naloxone given.

TABLE 12 Treatment Erythema Edema Other Total 2 mg (20 mg/mL, one spray)4 2 1 7 4 mg (20 mg/mL, two sprays) 1 0 0 1 4 mg (40 mg/mL, one spray) 12 0 3 8 mg (40 mg/mL, two sprays) 0 1 0 1

Table 1e shows additional events related to administration eithernasally or intramuscularly. Overall, few adverse events were reported.

TABLE 13 0.4 mg Intramuscular Dose Dizziness 1 Headache 1 Nausea 1 2 mg(20 mg/mL, one spray) Nasal Pain 1 8 mg (40 mg/mL, two sprays) Headache1

Additionally, vital signs, ECG, and clinical laboratory parameters didnot reveal any clinically noteworthy changes after naloxoneadministration. There was no evidence of QTcF prolongation.

Example 3 Naloxone Nasal Spray Formulations and Stability

Naloxone has been formulated as a disposable Luer-Jet Luer-lockpre-filled syringe and nasal atomizer kit product, comprising 1 mg/mlnaloxone hydrochloride as an active agent, 8.35 mg/ml NaCl as anisotonicity agent, HCl q.s. to target pH, and purified water q.s. to 2.0ml. Benzalkonium chloride may be added as a preservative, cationicsurfactant, and/or permeation enhancer, and supports the stability of amulti-dose product. Such syringes, while functional, can be ungainly touse by untrained personnel, and deliver a large volume of solution.

Examples of a 10 mg/ml formulation are given below in Table 14.

TABLE 14 Ingredient Quantity per unit Function Naloxone hydrochloride 10 mg/ml Active ingredient Sodium chloride 7.4 mg/ml Isotonicity agentHydrochloric acid q.s. to target pH Acidifying agent Benzalkoniumchloride 0.1 mg/ml Preservative, cationic surfactant, and/or permeationenhancer Purified water q.s. Solvent

Literature data has indicated that naloxone is sensitive toenvironmental factors, such as air, light and colours in certain vials,which may induce a risk for degradation. Consequently disodium edetatewas added to the above formulation.

Pharmaceutical compositions comprising naloxone hydrochloride (10 mg/mL)were stored at 25° C. and 60% relative humidity in upright clear glassvials (200 μL) stoppered with a black plunger. Vials were either nude(Batch 1), or mounted in the Pfeiffer BiDose device (Batch 2). Inaddition to naloxone hydrochloride, the pharmaceutical compositionsfurther comprised water, benzalkonium chloride, and disodium edetate.The vials were assayed at 0, 3, 6, 9, and 12 months for naloxonecontent. It is evident from the results of the study, reported as apercentage of the label claim in Table 15 below, that thesepharmaceutical compositions are storage-stable for at least 9-12 monthsat 25° C. and 60% relative humidity.

TABLE 15 Time (months) Batch 0 3 6 9 12 1 99.3 100.1 100.8 101.2 97.9 299.5 102.8 99.4 98.6 ND

Examples of 20 mg/ml and a 40 mg/ml formulation are given below in Table16, along with an example of permitted variation as part of the totalformulation.

TABLE 16 Concentration 20 mg/ml 40 mg/ml Quantity Quantity per unit perunit Quantity dose Quantity dose Product Component per ml (100 μl) perml (100 μl) Variation Naloxone HCl 22.0 mg 2.2 mg 44.0 mg 4.4 mg90.0-110.0 dihydrate (20.0 mg) (2.0 mg) (40.0 mg) (40.0 mg)(corresponding to naloxone HCl) Benzalkonium 0.1 mg 0.01 mg 0.1 mg 0.01mg 90.0-110.0 chloride Disodium edetate 2.0 mg  0.2 mg 2.0 mg  0.2 mg80.0-120.0 Sodium chloride 7.4 mg 0.74 mg 7.4 mg 0.74 mg HydrochloricAdjust to Adjust to Adjust to Adjust to pH 3.5-5.5 acid, dilute pH 4.5pH 4.5 pH 4.5 pH 4.5 Purified water q.s. ad 1.0 ml q.s. ad 100 μl q.s.ad q.s. ad 100 μl 1.0 ml

The naloxone hydrochloride nasal spray above is an aqueous solutionwhich may be presented in a Type I glass vial closed with a chlorobutylrubber plunger which in turn is mounted into a unit-dose nasal spraydevice (such as an Aptar UDS liquid UnitDose device). The solutionshould be a clear and colorless or slightly yellow liquid. In certainembodiments, the device is a non-pressurized dispenser delivering aspray containing a metered dose of the active ingredient. In certainembodiments, each delivered dose contains 100 μl.

Pharmaceutical compositions comprising naloxone hydrochloride (20 or 40mg/mL) were tested for stability in room temperature/light conditions,room temperature/dark conditions and in 25° C./60% RH (protected fromlight). It was tested for pH, purity, and impurities at an initial timepoint, 2 months and 10 months. Results are given in Table 17.

TABLE 17 Test Assay (% Storage interval of label Impurities condition(months) Appearance pH claim) (area %) Initial Clear, 4.5 101  Notdetected colourless solution 25° C./  2 Not analyzed 45 Not Not analyzed60% RH analyzed 10 Clear, 4.5 95 0.2 colourless solution Room 10 Clear,4.4 92 1.3 temperature/ yellow light solution Room 10 Clear, 4.5 97 0.3temperature/ colourless dark solution

Other Embodiments

The detailed description set-forth above is provided to aid thoseskilled in the art in practicing the present disclosure. However, thedisclosure described and claimed herein is not to be limited in scope bythe specific embodiments herein disclosed because these embodiments areintended as illustration of several aspects of the disclosure. Anyequivalent embodiments are intended to be within the scope of thisdisclosure. Indeed, various modifications of the disclosure in additionto those shown and described herein will become apparent to thoseskilled in the art from the foregoing description, which do not departfrom the spirit or scope of the present inventive discovery. Suchmodifications are also intended to fall within the scope of the appendedclaims.

What is claimed is:
 1. A pharmaceutical formulation for intranasaladministration comprising, in an aqueous solution of not more than about140 μL: about 4 mg naloxone hydrochloride; about 0.74 mg NaCl; about0.01 mg benzalkonium chloride; about 0.2 mg disodium edetate; and anamount of hydrochloric acid sufficient to achieve a pH of 3.5-5.5. 2.The pharmaceutical formulation of claim 1, wherein the aqueous solutionhas a volume of 100 μL.
 3. The pharmaceutical formulation of claim 1,which yields, when intranasally administered to a patient, a meannaloxone plasma concentration of ≧0.2 ng/mL within 2.5 minutes in saidpatient.
 4. The pharmaceutical formulation of claim 1, which yields,when intranasally administered to a patient, a mean naloxone plasmaconcentration of ≧1 ng/mL within 5 minutes in said patient.
 5. Thepharmaceutical formulation of claim 1, which yields, when intranasallyadministered to a patient, a mean naloxone plasma concentration of ≧3ng/mL within 10 minutes in said patient.
 6. The pharmaceuticalformulation of claim 1, which yields, when intranasally administered toa patient, a naloxone T_(max) of less than 30 minutes.
 7. Thepharmaceutical formulation of claim 1, which yields, when intranasallyadministered to a patient, a naloxone T_(max) of less than 25 minutes.8. The pharmaceutical formulation of claim 1, which yields, whenintranasally administered to a patient, a naloxone T_(max) of less than20 minutes.
 9. A method of treatment of opioid overdose or a symptomthereof, comprising: nasally administering to a patient in need thereofthe pharmaceutical formulation of claim
 1. 10. The method of claim 9,wherein upon nasal delivery of said pharmaceutical composition to saidpatient, less than about 20% of said pharmaceutical composition leavesthe nasal cavity via drainage into the nasopharynx or externally. 11.The method of claim 9, wherein upon nasal delivery of saidpharmaceutical composition to said patient, less than about 10% of saidpharmaceutical composition leaves the nasal cavity via drainage into thenasopharynx or externally.
 12. The method of claim 9, wherein upon nasaldelivery of said pharmaceutical composition to said patient, less thanabout 5% of said pharmaceutical composition leaves the nasal cavity viadrainage into the nasopharynx or externally.
 13. The method of claim 9,wherein the plasma concentration versus time curve of said naloxonehydrochloride in said patient has a T_(max) of between about 20 andabout 30 minutes.
 14. The method of claim 9, wherein the administrationyields a mean naloxone plasma concentration of ≧0.2 ng/mL within 2.5minutes in said patient.
 15. The method of claim 9, wherein theadministration yields a mean naloxone plasma concentration of ≧1 ng/mLwithin 5 minutes in said patient.
 16. The method of claim 9, wherein theadministration yields a mean naloxone plasma concentration of ≧3 ng/mLwithin 10 minutes in said patient.
 17. The method of claim 9, whereinsaid patient is an opioid overdose patient or a suspected opioidoverdose patient.
 18. The method of claim 17, wherein the patientexhibits one or more symptoms chosen from: respiratory depression,central nervous system depression, cardiovascular depression, alteredlevel consciousness, miotic pupils, hypoxemia, acute lung injury,aspiration pneumonia, sedation, hypotension, unresponsiveness tostimulus, unconsciousness, stopped breathing; erratic or stopped pulse,choking or gurgling sounds, blue or purple fingernails or lips, slack orlimp muscle tone, contracted pupils, and vomiting.
 19. The method ofclaim 17, wherein the patient exhibits respiratory depression.
 20. Asingle-use, pre-primed device adapted for nasal delivery of apharmaceutical composition to a patient by one actuation of said deviceinto one nostril of said patient, having a single reservoir comprising apharmaceutical composition which comprises per 100 μL of aqueoussolution: about 4 mg naloxone hydrochloride or a hydrate thereof;between about 0.2 mg and about 1.2 mg of an isotonicity agent; betweenabout 0.005 mg and about 0.015 mg of a preservative; between about 0.1mg and about 0.5 mg of a stabilizing agent; and an amount of an acidsufficient to achieve a pH of 3.5-5.5.
 21. The device as recited inclaim 20, wherein: the isotonicity agent is NaCl; the preservative isbenzalkonium chloride; the stabilizing agent is disodium edetate; andthe acid is hydrochloric acid.
 22. The device of claim 20, wherein theaqueous solution comprises per 100 μL: about 4 mg naloxonehydrochloride; about 0.74 mg NaCl; about 0.01 mg benzalkonium chloride;about 0.2 mg disodium edetate; and an amount of hydrochloric acidsufficient to achieve a pH of 3.5-5.5.
 23. The device of claim 20,wherein said device is actuatable with one hand.
 24. The device of claim20, wherein the volume of said reservoir is not more than about 140 μL.25. The device of claim 20, wherein about 100 μL of said aqueoussolution in said reservoir is delivered to said patient in oneactuation.
 26. The device of claim 20, wherein the pharmaceuticalcomposition which is an aqueous solution comprises about 4 mg naloxonehydrochloride.
 27. The device of claim 20, wherein the device isconfigured such that the 90% confidence interval for dose delivered peractuation is ±about 2%.
 28. The device of claim 20, wherein the deviceis configured such that the 95% confidence interval for dose deliveredper actuation is ±about 2.5%.
 29. The device of claim 20, wherein thedevice is configured such that the delivery time is less than about 25seconds.
 30. The device of claim 20, wherein the device is configuredsuch that the delivery time is less than about 20 seconds.